Trial Outcomes & Findings for Anhedonia, Development, and Emotions: Phenotyping and Therapeutics (NCT NCT05487885)
NCT ID: NCT05487885
Last Updated: 2026-03-17
Results Overview
This clinician-rated scale captures depression severity on a scale of 0-60, with higher scores reflecting greater severity
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
123 participants
Primary outcome timeframe
pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours)
Results posted on
2026-03-17
Participant Flow
Participant milestones
| Measure |
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.
|
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.
|
|---|---|---|
|
Phase 1
STARTED
|
26
|
97
|
|
Phase 1
COMPLETED
|
20
|
71
|
|
Phase 1
NOT COMPLETED
|
6
|
26
|
|
TMS and PAT
STARTED
|
0
|
50
|
|
TMS and PAT
COMPLETED
|
0
|
47
|
|
TMS and PAT
NOT COMPLETED
|
0
|
3
|
|
Ketamine
STARTED
|
0
|
24
|
|
Ketamine
COMPLETED
|
0
|
24
|
|
Ketamine
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
| Measure |
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.
|
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.
|
|---|---|---|
|
Phase 1
Withdrawal by Subject
|
1
|
7
|
|
Phase 1
Lost to Follow-up
|
1
|
11
|
|
Phase 1
Not Phase 2 Eligible
|
4
|
0
|
|
Phase 1
Removed by PI
|
0
|
5
|
|
Phase 1
Participant moved
|
0
|
1
|
|
Phase 1
Waitlisted
|
0
|
2
|
|
TMS and PAT
Lost to Follow-up
|
0
|
1
|
|
TMS and PAT
Withdrawal by Subject
|
0
|
2
|
Baseline Characteristics
Anhedonia, Development, and Emotions: Phenotyping and Therapeutics
Baseline characteristics by cohort
| Measure |
Phase 1 Only
n=26 Participants
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.
|
Phase 1, Then Phase 2
n=97 Participants
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.
|
Total
n=123 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
>=65 years
|
0 Participants
n=10 Participants
|
0 Participants
n=50 Participants
|
0 Participants
n=108 Participants
|
|
Age, Categorical
<=18 years
|
2 Participants
n=10 Participants
|
2 Participants
n=50 Participants
|
4 Participants
n=108 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
24 Participants
n=10 Participants
|
95 Participants
n=50 Participants
|
119 Participants
n=108 Participants
|
|
Age, Continuous
|
20.73 years
STANDARD_DEVIATION 2.68 • n=10 Participants
|
21.28 years
STANDARD_DEVIATION 2.22 • n=50 Participants
|
21.16 years
STANDARD_DEVIATION 2.32 • n=108 Participants
|
|
Sex: Female, Male
Female
|
21 Participants
n=10 Participants
|
85 Participants
n=50 Participants
|
106 Participants
n=108 Participants
|
|
Sex: Female, Male
Male
|
5 Participants
n=10 Participants
|
12 Participants
n=50 Participants
|
17 Participants
n=108 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=10 Participants
|
7 Participants
n=50 Participants
|
9 Participants
n=108 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
24 Participants
n=10 Participants
|
90 Participants
n=50 Participants
|
114 Participants
n=108 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=10 Participants
|
0 Participants
n=50 Participants
|
0 Participants
n=108 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=10 Participants
|
0 Participants
n=50 Participants
|
0 Participants
n=108 Participants
|
|
Race (NIH/OMB)
Asian
|
3 Participants
n=10 Participants
|
12 Participants
n=50 Participants
|
15 Participants
n=108 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=10 Participants
|
0 Participants
n=50 Participants
|
0 Participants
n=108 Participants
|
|
Race (NIH/OMB)
Black or African American
|
2 Participants
n=10 Participants
|
6 Participants
n=50 Participants
|
8 Participants
n=108 Participants
|
|
Race (NIH/OMB)
White
|
20 Participants
n=10 Participants
|
76 Participants
n=50 Participants
|
96 Participants
n=108 Participants
|
|
Race (NIH/OMB)
More than one race
|
1 Participants
n=10 Participants
|
3 Participants
n=50 Participants
|
4 Participants
n=108 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=10 Participants
|
0 Participants
n=50 Participants
|
0 Participants
n=108 Participants
|
|
Region of Enrollment
United States
|
26 participants
n=10 Participants
|
97 participants
n=50 Participants
|
123 participants
n=108 Participants
|
PRIMARY outcome
Timeframe: pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours)Population: 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).
This clinician-rated scale captures depression severity on a scale of 0-60, with higher scores reflecting greater severity
Outcome measures
| Measure |
Phase 2: TMS and PAT
n=48 Participants
All open label with no randomization to placebo. Single arm.
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.
|
Phase 2: Ketamine
n=24 Participants
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.
|
|---|---|---|
|
Montgomery-Asberg Depression Rating Scale (MADRS) Score
Pre-treatment
|
28.9 score on a scale
Standard Deviation 6.54
|
24.9 score on a scale
Standard Deviation 4.1
|
|
Montgomery-Asberg Depression Rating Scale (MADRS) Score
Post-treatment
|
21.4 score on a scale
Standard Deviation 7.33
|
20.7 score on a scale
Standard Deviation 7.1
|
SECONDARY outcome
Timeframe: pre- to post-TMS (over 2 weeks) and pre- to post-ketamine (24 hours)Population: 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).
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.
Outcome measures
| Measure |
Phase 2: TMS and PAT
n=48 Participants
All open label with no randomization to placebo. Single arm.
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.
|
Phase 2: Ketamine
n=23 Participants
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.
|
|---|---|---|
|
Snaith Hamilton Pleasure Scale (SHAPS) Score
Pre-treatment
|
34.5 score on a scale
Standard Deviation 6.58
|
34.2 score on a scale
Standard Deviation 7.8
|
|
Snaith Hamilton Pleasure Scale (SHAPS) Score
Post-treatment
|
31.3 score on a scale
Standard Deviation 6.81
|
33.3 score on a scale
Standard Deviation 7.9
|
Adverse Events
TMS and PAT
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Ketamine
Serious events: 0 serious events
Other events: 4 other events
Deaths: 0 deaths
Phase 1
Serious events: 0 serious events
Other events: 23 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
TMS and PAT
n=50 participants at risk
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.
|
Ketamine
n=24 participants at risk
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.
|
Phase 1
n=123 participants at risk
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.
|
|---|---|---|---|
|
Gastrointestinal disorders
Vomiting/Nausea
|
0.00%
0/50 • The duration of the study per person was generally up to 1 year.
|
12.5%
3/24 • Number of events 3 • The duration of the study per person was generally up to 1 year.
|
0.00%
0/123 • The duration of the study per person was generally up to 1 year.
|
|
Nervous system disorders
Pain/Discomfort
|
2.0%
1/50 • Number of events 1 • The duration of the study per person was generally up to 1 year.
|
0.00%
0/24 • The duration of the study per person was generally up to 1 year.
|
0.00%
0/123 • The duration of the study per person was generally up to 1 year.
|
|
Nervous system disorders
MRI Scan Incidental Finding
|
0.00%
0/50 • The duration of the study per person was generally up to 1 year.
|
0.00%
0/24 • The duration of the study per person was generally up to 1 year.
|
1.6%
2/123 • Number of events 4 • The duration of the study per person was generally up to 1 year.
|
|
Psychiatric disorders
Suicidality Ideation
|
4.0%
2/50 • Number of events 2 • The duration of the study per person was generally up to 1 year.
|
4.2%
1/24 • Number of events 1 • The duration of the study per person was generally up to 1 year.
|
17.1%
21/123 • Number of events 22 • The duration of the study per person was generally up to 1 year.
|
Additional Information
Dr. Erika Forbes
University of Pittsburgh Medical Center, Department of Psychiatry
Phone: 412-383-5438
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place