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The goal of the ADEPT Study is to understand anhedonia in young people and how it changes based on treatments targeting the brain circuit underlying it. Anhedonia is a challenging mental health symptom that involves difficulty with motivation to experience pleasant events. This study could help develop treatments for people whose depression does not improve with traditional treatments.
The ADEPT Study includes two phases. In Phase 1, participants are asked to go through a series of activities to measure anhedonia, including MRI scans, blood draws, behavioral tasks, clinical interviews, questionnaires, and app-based assessments of experiences and behaviors. Phase 2 involves therapeutic activities, such as transcranial magnetic stimulation (TMS), positive affect training, and, for some people, ketamine administration. If the participant qualifies and is interested, they may choose to do Phase 2 activities in addition to Phase 1.
In this research study, the investigators are trying to understand and change anhedonia in young people with depression. Anhedonia is experienced by many people who have depression, and it involves difficulty with motivation, energy, and anticipation of pleasant events. People who experience anhedonia often have more severe depression, experience depression for longer periods of time, and don't easily get better with traditional treatments. The investigators want to understand anhedonia early in life in order to help young people develop along healthy pathways and avoid chronic illness. Anhedonia is related to function in the brain's reward circuit, inflammation in the body, and people's experiences and behaviors, and will measure all of these. The investigators also want to understand anhedonia by using treatments that could improve it. To do that, activities will be used that have been used to treat depression and target the brain's reward circuit, which is believed to be the source of anhedonia. Finally, anhedonia will be measured over approximately 1 year to see how it changes with time, development, or treatment-based experiences. Eventually, the findings of this study might be useful for treating depression and improving people's quality of life.
The study is looking for 300 young people (aged 15-25) who are currently experiencing depression to participate in our research study. In Phase 1 of our study, a series of activities will be conducted to understand the characteristics of anhedonia, including MRI scans, blood draws, behavioral tasks, clinical interviews, questionnaires, and measurement of real-life experiences and behavior using a phone app. This is called "phenotyping" because these characteristics are also called phenotypes.
The eligibility process for Phase 1 will include an interview with questions about the participant's mood, experiences, and behaviors. This interview will take approximately 2-3 hours. With permission, interviews will be video recorded to facilitate training and supervision of study staff. Participants will also be asked questions about health, including treatment history.
Study procedures include 4 visits over approximately 1 year. These may be broken into two sessions per visit for scheduling reasons. In addition, the study will include an ongoing smartphone app-based assessment of mood, experiences, and behavior.
Visit 1 consists of an MRI scan, questionnaires about thoughts, emotions, and experiences, tasks on a computer and a blood draw by a trained phlebotomist. Visits 2-4 consists of a second MRI scan, questionnaires, tasks on a computer, a blood draw by a trained phlebotomist, and an interview about mood, experiences, and behaviors.
Phase 2 of this study involves procedures that are therapeutic, meaning they can treat depression and anhedonia. These include transcranial magnetic stimulation (TMS), which is a noninvasive procedure to treat depression that uses magnetic fields to stimulate nerve cells in the brain. Visits with TMS will include Positive Affect Training, which involves changing behaviors and thoughts to build positive emotions. People whose depression does not improve with TMS may receive a single intravenous (IV, or into the vein) infusion of ketamine, a medicine that is used in hospitals for anesthesia and that can improve depression quickly.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TMS and PAT | Experimental | All open label with no randomization to placebo |
|
| TMS and PAT, then Ketamine | Experimental | All open label with no randomization to placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Continuous theta burst stimulation (cTBS) | Device | a form of transcranial magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale (MADRS) Score | This clinician-rated scale captures depression severity on a scale of 0-60, with higher scores reflecting greater severity | pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours) |
| Measure | Description | Time Frame |
|---|---|---|
| Snaith Hamilton Pleasure Scale (SHAPS) Score | This 14-item self-report questionnaire measures anhedonia, or difficulty with motivation toward or enjoyment of pleasant events. Total scores range from 14-56, with higher scores reflecting greater severity. | pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours) |
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Inclusion Criteria:
Phase 1 (all participants)
Phase 2 (for participants in TBS and ketamine phase, in addition to above)
• ≥ 1 failed antidepressant trial (for qualification for Phase 2 of study and definition of non-response to TMS in order 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:
Phase 1 (all participants)
Phase 2 (for participants in TBS and ketamine phase, in addition to above)
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| Name | Affiliation | Role |
|---|---|---|
| Erika E Forbes, PhD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Loeffler Building | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19561255 | Background | Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, Savoiardo M, Chiapparini L. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology. 2009 Jul;252(1):165-72. doi: 10.1148/radiol.2522081399. | |
| 29106542 | Background | Belujon P, Grace AA. Dopamine System Dysregulation in Major Depressive Disorders. Int J Neuropsychopharmacol. 2017 Dec 1;20(12):1036-1046. doi: 10.1093/ijnp/pyx056. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Phase 1 Only | No treatment. Observational only. Single arm. Phase 1 involved collecting phenotype data (did not involve TMS nor ketamine injection). Study procedures included an interview visit, questionnaires, and MRI scan. |
| FG001 | Phase 1, Then Phase 2 | TBS+PAT; or TBS+PAT, then Ketamine All open label with no randomization to placebo. Single arm. Participants completed phase 1 and proceeded to phase 2 (treatment, TMS+PAT). Participants who do not respond to TMS+PAT (<50% decrease in MADRS + MADRS<11) will receive a single dose of ketamine. Continuous theta burst stimulation (cTBS): a form of transcranial magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC) Positive Affect Training: Psychosocial add-on intervention that could enhance the effects of TBS. PA Therapy (Craske et al., 2016) is an innovative cognitive and experiential technique designed to address anhedonia and change altered patterns of brain function. PA training has efficacy for enhancing positive affect and reducing negative affect (Craske et al., 2018). Ketamine Injectable Solution: The FDA-approved anesthetic agent will be used off-label in this study. It is used routinely in both pediatric and adult patients and is considered extremely safe in substantially higher, anesthetic doses. The dose to be administered here (0.5 mg/kg) is a much lower, subanesthetic dose, and the administration route (intravenous) is the standard when used in anesthesia. Published studies and metaanalyses of this dose as an off label use in depression show that there are no increased risks in this population, including in adolescents (Dwyer et al, 2021, Am J Psychiatry). A single dose of ketamine will be used to determine if it alters depression and anhedonia. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 |
|
| |||||||||||||||||||||
| TMS and PAT |
| ||||||||||||||||||||||
| Ketamine |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Phase 1 Only | All open label with no randomization to placebo. Single arm. Phase 1 Only group does not receive treatment. Measurement of characteristics related to depression and anhedonia. Study procedures included an interview visit and MRI scan. |
| BG001 | Phase 1, Then Phase 2 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Montgomery-Asberg Depression Rating Scale (MADRS) Score | This clinician-rated scale captures depression severity on a scale of 0-60, with higher scores reflecting greater severity | Fifty participants initiated TMS; 48 had evaluable pre- and post-TMS MADRS data and were analyzed; two discontinued prior to assessment. Twenty-four subsequently completed ketamine with evaluable pre- and post-ketamine MADRS data. Analyses were restricted to Phase 2 participants (N≤50). | Posted | Mean | Standard Deviation | score on a scale | pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours) |
|
The duration of the study per person was generally up to 1 year.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TMS and PAT | All open label with no randomization to placebo Continuous theta burst stimulation (cTBS): a form of transcranial magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC) Positive Affect Training: 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting/Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Erika Forbes | University of Pittsburgh Medical Center, Department of Psychiatry | 412-383-5438 | forbese@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 19, 2025 | Dec 17, 2025 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 22, 2024 | Jul 16, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D003863 | Depression |
| D059445 | Anhedonia |
| ID | Term |
|---|---|
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
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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. This set of 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: (1) 10 theta burst stimulation (TBS) sessions (TBS 2 times/session) plus positive affect (PA) training for all participants; and (2) IV ketamine infusion for those who do not respond to TBS/PA activities.
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| Positive Affect Training | Behavioral | 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. |
|
| Ketamine Injectable Solution | Drug | Ketamine is FDA-approved as an anesthetic agent that will be used off-label in this study. It is used routinely in both pediatric and adult patients and is considered extremely safe in substantially higher, anesthetic doses. The dose to be administered here (0.5 mg/kg) is a much lower, subanesthetic dose, and the administration route (intravenous) is the standard when used in anesthesia. Published studies and metaanalyses of this dose of intravenous ketamine as an off label use in depression show clearly that there are no increased risks in this population, including a recent study in adolescents (Dwyer et al, 2021, American Journal of Psychiatry). A single dose of ketamine will be used to determine if it alters the functioning of the anhedonia-related reward functioning and frontostriatal biomarkers assessed in this study. |
|
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| 33243615 | Background | Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24. |
| 7551619 | Background | Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99. |
| 20167473 | Background | Somerville LH, Casey BJ. Developmental neurobiology of cognitive control and motivational systems. Curr Opin Neurobiol. 2010 Apr;20(2):236-41. doi: 10.1016/j.conb.2010.01.006. Epub 2010 Feb 16. |
| 29644335 | Background | Sulzer D, Cassidy C, Horga G, Kang UJ, Fahn S, Casella L, Pezzoli G, Langley J, Hu XP, Zucca FA, Isaias IU, Zecca L. Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson's disease. NPJ Parkinsons Dis. 2018 Apr 10;4:11. doi: 10.1038/s41531-018-0047-3. eCollection 2018. |
| 19672310 | Background | Treadway MT, Buckholtz JW, Schwartzman AN, Lambert WE, Zald DH. Worth the 'EEfRT'? The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PLoS One. 2009 Aug 12;4(8):e6598. doi: 10.1371/journal.pone.0006598. |
| 20603146 | Background | Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011 Jan;35(3):537-55. doi: 10.1016/j.neubiorev.2010.06.006. Epub 2010 Jul 11. |
| 22051807 | Background | Wang Y, Butros SR, Shuai X, Dai Y, Chen C, Liu M, Haacke EM, Hu J, Xu H. Different iron-deposition patterns of multiple system atrophy with predominant parkinsonism and idiopathetic Parkinson diseases demonstrated by phase-corrected susceptibility-weighted imaging. AJNR Am J Neuroradiol. 2012 Feb;33(2):266-73. doi: 10.3174/ajnr.A2765. Epub 2011 Nov 3. |
| 32078260 | Background | Wang L, Li F, Mitchell PB, Wang CY, Si TM. Striatal Resting-State Connectivity Abnormalities Associated With Different Clinical Stages of Major Depressive Disorder. J Clin Psychiatry. 2020 Feb 18;81(2):19m12790. doi: 10.4088/JCP.19m12790. |
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| 26455458 | Background | Zucca FA, Segura-Aguilar J, Ferrari E, Munoz P, Paris I, Sulzer D, Sarna T, Casella L, Zecca L. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol. 2017 Aug;155:96-119. doi: 10.1016/j.pneurobio.2015.09.012. Epub 2015 Oct 9. |
| Not Phase 2 Eligible |
|
| Removed by PI |
|
| Participant moved |
|
| Waitlisted |
|
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
TMS and PAT, then Ketamine All open label with no randomization to placebo. Single arm. Participants who do not respond to cTBS+PA (<50% decrease in MADRS + MADRS<11) will receive a single dose of ketamine. Continuous theta burst stimulation (cTBS): a form of transcranial magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC) Positive Affect Training: Psychosocial add-on intervention that could enhance the effects of TBS. PA Therapy (Craske et al., 2016) is an innovative cognitive and experiential technique designed to address anhedonia and change altered patterns of brain function. PA training has efficacy for enhancing positive affect and reducing negative affect (Craske et al., 2018). Ketamine Injectable Solution: The FDA-approved anesthetic agent will be used off-label in this study. It is used routinely in both pediatric and adult patients and is considered extremely safe in substantially higher, anesthetic doses. The dose to be administered here (0.5 mg/kg) is a much lower, subanesthetic dose, and the administration route (intravenous) is the standard when used in anesthesia. Published studies and metaanalyses of this dose as an off label use in depression show that there are no increased risks in this population, including in adolescents (Dwyer et al, 2021, Am J Psychiatry). A single dose of ketamine will be used to determine if it alters depression and anhedonia. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Phase 2: Ketamine | All open label with no randomization to placebo. Single arm. Participants who do not respond to cTBS+PA (<50% decrease in MADRS + MADRS<11) will receive a single dose of ketamine Continuous theta burst stimulation (cTBS): a form of transcranial magnetic stimulation, to dorsomedial prefrontal cortex (dmPFC) Positive Affect Training: Psychosocial add-on intervention that could enhance the effects of TBS. PA Therapy (Craske et al., 2016) is an innovative cognitive and experiential technique designed to address anhedonia and change altered patterns of brain function. PA training has efficacy for enhancing positive affect and reducing negative affect (Craske et al., 2018). Ketamine Injectable Solution: This FDA-approved anesthetic agent will be used off-label in this study. It is used routinely in both pediatric and adult patients and is considered extremely safe in substantially higher, anesthetic doses. The dose to be administered here (0.5 mg/kg) is a much lower, subanesthetic dose, and the administration route (intravenous) is the standard when used in anesthesia. Published studies and metaanalyses of this dose as an off label use in depression show that there are no increased risks in this population, including in adolescents (Dwyer et al, 2021, Am J Psychiatry). A single dose of ketamine will be used to determine if it alters depression and anhedonia. |
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|
|
| Secondary | Snaith Hamilton Pleasure Scale (SHAPS) Score | This 14-item self-report questionnaire measures anhedonia, or difficulty with motivation toward or enjoyment of pleasant events. Total scores range from 14-56, with higher scores reflecting greater severity. | Fifty participants initiated TMS; 48 had evaluable pre- and post-TMS SHAPS data and were analyzed, while two discontinued prior to assessment. Of these, 24 completed ketamine, and 23 had evaluable pre- and post-ketamine SHAPS data. Analyses were limited to Phase 2 participants (N≤50). | Posted | Mean | Standard Deviation | score on a scale | pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours) |
|
|
|
|
| 0 |
| 50 |
| 0 |
| 50 |
| 3 |
| 50 |
| EG001 | Ketamine | Ketamine Injectable Solution: Ketamine is FDA-approved as an anesthetic agent that will be used off-label in this study. It is used routinely in both pediatric and adult patients and is considered extremely safe in substantially higher, anesthetic doses. The dose to be administered here (0.5 mg/kg) is a much lower, subanesthetic dose, and the administration route (intravenous) is the standard when used in anesthesia. Published studies and metaanalyses of this dose of intravenous ketamine as an off label use in depression show clearly that there are no increased risks in this population, including a recent study in adolescents (Dwyer et al, 2021, American Journal of Psychiatry). A single dose of ketamine will be used to determine if it alters the functioning of the anhedonia-related reward functioning and frontostriatal biomarkers assessed in this study. | 0 | 24 | 0 | 24 | 4 | 24 |
| EG002 | Phase 1 | Phenotyping assessments. Phase 1 consists of the baseline visit, either before treatment for the group that intended to receive treatment (Phase 2 group) or for phenotyping for the group that did not give consent for treatment (Phase 1 Only group; n=26). Assessment included interview, questionnaires, and fMRI. All 123 participants enrolled (regardless of group) completed Phase 1 assessments. | 0 | 123 | 0 | 123 | 23 | 123 |
| Pain/Discomfort | Nervous system disorders | Systematic Assessment |
|
| MRI Scan Incidental Finding | Nervous system disorders | Systematic Assessment |
|
| Suicidality Ideation | Psychiatric disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D009422 |
| Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
This tests change post-TMS to post-ketamine for participants who received ketamine |
| ANOVA |
Repeated measures ANOVA F(1,22) = 0.7, p=0.407 |
| 0.407 |
| Mean Difference (Final Values) |
| 0.8 |
| Standard Deviation |
| 4.7 |
| 2-Sided |
| Other |