Major Depressive Disorder (MDD)Early Phase 1NCT06788249
Pilot Study: Establishing Glutamatergic Changes in Rapid Antidepressant Effects of Ketamine
A Early Phase 1 study testing Ketamine only in people with Major Depressive Disorder (MDD), run by University of Pennsylvania at 1 site in United States.
Trial summary
In the treatment of Major Depressive Disorder (MDD), ketamine can produce rapid but short-lasting improvements in mood. In order to develop a new generation of treatments with rapid and sustained efficacy, a better understanding of the mechanism of action is urgently needed. Read more about this study
- Who is it for?
- Ages 25 to 65 years
- Conditions the study is for
- Major Depressive Disorder (MDD)
- What is being tested?
- Ketamine only
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Apr 2026to 15 Dec 2026
- Phase
- Early Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age between 25 and 65 years;
- Current depression as assessed on the SCID;
- Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode. Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks
- Able to comprehend English, as all questionnaires are in this language
- Ability to provide informed consent Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.
Who cannot join
- A sleep disorder other than insomnia, as determined by history;
- History of bipolar disorder, delirium, dementia, amnestic disorder, schizophrenia and other psychotic disorders as assessed on the SCID;
- Alcohol or drug abuse in the past year based upon the SCID or urine toxicology screen;
- A current smoker;
- 4) Any significant medical or neurological illness that impacts brain function or impedes participation; 5) History of head trauma with significant loss of consciousness; 6) Metallic implants, pacemakers or tattoos, or other contraindications to MRI; Claustrophobic, or intolerant of the scanner environment; 7) For women, pregnancy will exclude participation. 8) Untreated hypertension
- Based on ketamine's known difficulties with induction of perceptual/psychomimetic symptoms, exclusion criteria for this study are as follows:
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- Patients with a BMI over 40.
- Ongoing prescription of 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment;
- Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression;
- Use of any MAOI is prohibited two weeks prior to administration of study drug; if patients are on an MAOI when enrolled, study drug will not be administered until two weeks off MAOI;
- CYP3A4 inducers carbamazepine and modafinil are prohibited two weeks prior to administration of study drug and at least 24 hours after last dose of study drug.
- Current use of Naltrexone;
- Developmental delay, mental retardation, or intellectual disorder;
- Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months;
- Prior participation in another study of ketamine for depression
- Prior treatment and/or recreational use of ketamine
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Holly Barilla, MS contact
United States1 site, 1 recruiting
- Recruiting
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Isabel Koh, 215-573-6173, Isabel.Koh@PennMedicine.upenn.edu
Jennifer Goldschmied, PhD
About this study
Official title: Establishing Glutamatergic Changes as the Mechanism of Action in the Rapid Antidepressant Effects of Ketamine
In the treatment of Major Depressive Disorder (MDD), ketamine can produce rapid but short-lasting improvements in mood. In order to develop a new generation of treatments with rapid and sustained efficacy, a better understanding of the mechanism of action is urgently needed. One candidate mechanism is the modulation of synaptic strength mediated by glutamatergic activity as ketamine has been suggested to increase synaptic strength. Although determining how ketamine impacts the glutamatergic system is essential to isolating its mechanism of action, the invasive nature of most assessment methods has limited our ability to do so in humans. The proposed research aims to determine if changes in glutamatergic activity, reflecting the modulation of synaptic strength, underlie the antidepressant effects of ketamine. In this project, the investigators will utilize a novel measure of glutamate imaging, GluCEST, to assess changes in glutamatergic activity to assess synaptic strength following ketamine administration. Ten individuals (aged 25-65) with a DSM-V diagnosis of MDD will undergo baseline GluCEST imaging prior to and following ketamine infusion. Both clinician-administered and subjective mood measures will be collected. It is predicted that ketamine will improve mood and increase glutamatergic activity and synaptic strength. Results from this project have the potential to identify the modifiable mechanisms by which rapid antidepressants work which could ultimately stimulate the development of novel interventions that work through the modulation of glutamatergic activity.
Read the detailed description
Consent and Virtual Screening: Participants who meet initial inclusion criteria via phone screen will be invited to the complete a virtual visit that will include additional screening (e.g. Medical history), Structured Clinical Interview for DSMV (SCID) and clinician-administered measures of mood to determine final study eligibility. At the outset of this visit, all participants will receive verbal and written explanation of the general goals and risks of the study and will virtually sign an informed consent.
The results of the SCID will be used to characterize the study population and to determine whether they meet criteria for any diagnoses that would preclude participation (e.g. psychotic disorders). Their medical history will be reviewed by a study staff member to ensure that patients are diagnostically eligible.
At-home Sleep Recording: Following enrollment participants will complete a 7-day at-home sleep diary to assess sleep patterns prior to ketamine infusion. Sleep diaries will be completed either online via REDCap or with paper forms, based on participant preference and internet access.
In-laboratory Ketamine Infusion Protocol: On the study day, participants will arrive at the Hospital of the University of Pennsylvania at 9:00 AM. After initial orientation, they will undergo a baseline MRI scan between 9:00 AM and 11:00 AM. The MRI will utilize a 7T Siemens Terra system for high-resolution GluCEST imaging to capture glutamatergic activity. Following the scan, participants will complete baseline mood assessments, including the HAM-D, PANAS, VAS, and POMS scales. A light snack will be provided before the ketamine infusion begins between 12:00 PM and 1:00 PM. Participants will receive a 40-minute infusion of ketamine (0.5 mg/kg) under the supervision of a registered nurse and anesthesiologist. Continuous monitoring of vital signs (blood pressure, heart rate, oxygen levels) will be performed throughout the infusion. If adverse symptoms arise, the infusion may be paused or stopped at the discretion of the study physician. Following the infusion, participants will be observed for 1 hour to ensure stable vitals and recovery. Mood assessments will be repeated after the infusion to measure changes in emotional state. A second MRI scan will be conducted between 4:00 PM and 6:00 PM to assess changes in glutamatergic activity post-infusion. After completing the scan and final assessments, participants will be discharged.
- Conditions
- Major Depressive Disorder (MDD)
- Being tested
- Ketamine only
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketamine onlyDrug
The primary study intervention involves the administration of intravenous ketamine (0.5 mg/kg) over a 40-minute infusion. Ketamine, an NMDA receptor antagonist, has shown rapid antidepressant effects in individuals with treatment-resistant depression.
| Study group | Role | What they receive |
|---|---|---|
| Major Depressive Disorder | Experimental | Not described Receives: Drug: Ketamine only |
What is being measured
The primary outcome is the main question the study is designed to answer.
GluCEST imaging metrics
relative change in glutamate concentration (% baseline)
Measured: From pre to post-ketamine infusion (2 imaging sessions over a 9-hour span)
Secondary outcomes (1)
Hamilton Depression Rating Scale
Assessment of severity and change in depressive symptoms, from 0-52, with 52 indicating most severe
Measured: From pre to post-ketamine infusion (2 evaluations over a 9-hour span)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2025
- Study start1 Apr 2026
- Primary completion15 Dec 2026 (estimated)
- Study completion15 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive Disorder (MDD)Studies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single Group Assignment
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jennifer R Goldschmied, PhD, Principal investigator, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06788249
- Sponsor's protocol ID
- 857228
- Status last verified
- Oct 2026
- First submitted
- 16 Jan 2025
- Last updated
- 7 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Establishing Glutamatergic Changes as the Mechanism of Action in the Rapid Antidepressant Effects of Ketamine
- ClinicalTrials.gov ID
- NCT06788249
- Acronym / sponsor ID
- 857228
- Conditions
- Major Depressive Disorder (MDD)
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Study start
- 1 Apr 2026 (actual)
- Primary completion
- 15 Dec 2026 (estimated)
- Study completion
- 15 Dec 2026 (estimated)
- First posted
- 23 Jan 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In the treatment of Major Depressive Disorder (MDD), ketamine can produce rapid but short-lasting improvements in mood. In order to develop a new generation of treatments with rapid and sustained efficacy, a better understanding of the mechanism of action is urgently needed. One candidate mechanism is the modulation of synaptic strength mediated by glutamatergic activity as ketamine has been suggested to increase synaptic strength. Although determining how ketamine impacts the glutamatergic system is essential to isolating its mechanism of action, the invasive nature of most assessment methods has limited our ability to do so in humans. The proposed research aims to determine if changes in glutamatergic activity, reflecting the modulation of synaptic strength, underlie the antidepressant effects of ketamine. In this project, the investigators will utilize a novel measure of glutamate imaging, GluCEST, to assess changes in glutamatergic activity to assess synaptic strength following ketamine administration. Ten individuals (aged 25-65) with a DSM-V diagnosis of MDD will undergo baseline GluCEST imaging prior to and following ketamine infusion. Both clinician-administered and subjective mood measures will be collected. It is predicted that ketamine will improve mood and increase glutamatergic activity and synaptic strength. Results from this project have the potential to identify the modifiable mechanisms by which rapid antidepressants work which could ultimately stimulate the development of novel interventions that work through the modulation of glutamatergic activity.
Detailed description
Consent and Virtual Screening: Participants who meet initial inclusion criteria via phone screen will be invited to the complete a virtual visit that will include additional screening (e.g. Medical history), Structured Clinical Interview for DSMV (SCID) and clinician-administered measures of mood to determine final study eligibility. At the outset of this visit, all participants will receive verbal and written explanation of the general goals and risks of the study and will virtually sign an informed consent.
The results of the SCID will be used to characterize the study population and to determine whether they meet criteria for any diagnoses that would preclude participation (e.g. psychotic disorders). Their medical history will be reviewed by a study staff member to ensure that patients are diagnostically eligible.
At-home Sleep Recording: Following enrollment participants will complete a 7-day at-home sleep diary to assess sleep patterns prior to ketamine infusion. Sleep diaries will be completed either online via REDCap or with paper forms, based on participant preference and internet access.
In-laboratory Ketamine Infusion Protocol: On the study day, participants will arrive at the Hospital of the University of Pennsylvania at 9:00 AM. After initial orientation, they will undergo a baseline MRI scan between 9:00 AM and 11:00 AM. The MRI will utilize a 7T Siemens Terra system for high-resolution GluCEST imaging to capture glutamatergic activity. Following the scan, participants will complete baseline mood assessments, including the HAM-D, PANAS, VAS, and POMS scales. A light snack will be provided before the ketamine infusion begins between 12:00 PM and 1:00 PM. Participants will receive a 40-minute infusion of ketamine (0.5 mg/kg) under the supervision of a registered nurse and anesthesiologist. Continuous monitoring of vital signs (blood pressure, heart rate, oxygen levels) will be performed throughout the infusion. If adverse symptoms arise, the infusion may be paused or stopped at the discretion of the study physician. Following the infusion, participants will be observed for 1 hour to ensure stable vitals and recovery. Mood assessments will be repeated after the infusion to measure changes in emotional state. A second MRI scan will be conducted between 4:00 PM and 6:00 PM to assess changes in glutamatergic activity post-infusion. After completing the scan and final assessments, participants will be discharged.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single Group Assignment
| Arm | Type | Receives |
|---|---|---|
| Major Depressive Disorder | Experimental | Drug: Ketamine only |
Who may qualify
- Ages
- 25 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age between 25 and 65 years;
- Current depression as assessed on the SCID;
- Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode. Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks
- Able to comprehend English, as all questionnaires are in this language
- Ability to provide informed consent Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.
Key exclusion criteria (16 listed)
- A sleep disorder other than insomnia, as determined by history;
- History of bipolar disorder, delirium, dementia, amnestic disorder, schizophrenia and other psychotic disorders as assessed on the SCID;
- Alcohol or drug abuse in the past year based upon the SCID or urine toxicology screen;
- A current smoker;
- 4) Any significant medical or neurological illness that impacts brain function or impedes participation; 5) History of head trauma with significant loss of consciousness; 6) Metallic implants, pacemakers or tattoos, or other contraindications to MRI; Claustrophobic, or intolerant of the scanner environment; 7) For women, pregnancy will exclude participation. 8) Untreated hypertension
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketamine onlyThe primary study intervention involves the administration of intravenous ketamine (0.5 mg/kg) over a 40-minute infusion. Ketamine, an NMDA receptor antagonist, has shown rapid antidepressant effects in individuals with treatment-resistant depression. | Drug | Major Depressive Disorder |
Primary outcome
GluCEST imaging metrics
Time frame: From pre to post-ketamine infusion (2 imaging sessions over a 9-hour span)
relative change in glutamate concentration (% baseline)
1 secondary outcome
Hamilton Depression Rating Scale
Time frame: From pre to post-ketamine infusion (2 evaluations over a 9-hour span)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Oct 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Holly Barilla, MS contact
Jennifer R Goldschmied, PhD principal investigator
University of Pennsylvania
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Ketamine only in people with Major Depressive Disorder (MDD), run by University of Pennsylvania at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 7 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Isabel Koh (215-573-6173, Isabel.Koh@PennMedicine.upenn.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
GluCEST imaging metrics (time frame: From pre to post-ketamine infusion (2 imaging sessions over a 9-hour span)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2026.