Measuring glutamate changes after ketamine to explain its fast antidepressant effects

Establishing Glutamatergic Changes as the Mechanism of Action in the Rapid Antidepressant Effects of Ketamine

This trial will see if ketamine produces measurable changes in brain glutamate in adults with treatment-resistant major depressive disorder using high-field GluCEST imaging.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 25 Years to 65 Years
• Sex: All
• Sponsor: University of Pennsylvania (Academic / other)
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT06788249 on ClinicalTrials.gov

What this trial studies

Participants with treatment-resistant major depressive disorder will be screened virtually and complete diagnostic interviews and a 7-day sleep diary before an in-person study visit. On the study day they will undergo baseline GluCEST imaging on a 7T MRI, receive a ketamine infusion, and have follow-up imaging and mood assessments to track rapid biochemical and clinical changes. The protocol excludes people with bipolar or psychotic disorders, recent substance abuse, current smoking, or significant medical conditions. This pilot early-phase study aims to link glutamatergic signal changes to ketamine's antidepressant effects to inform future treatment development.

Who should consider this trial

Good fit: Adults aged 25 to 65 with current, treatment-resistant major depressive disorder (failure of at least two adequate antidepressant or mood‑stabilizing treatments), who speak English and meet medical and psychiatric eligibility criteria, are ideal candidates.

Not a fit: People with bipolar disorder, psychotic disorders, recent alcohol or drug abuse, current smokers, certain sleep disorders, or significant medical conditions are excluded and would not be eligible to participate or likely benefit from this protocol.

Why it matters

Potential benefit: If successful, the findings could point to new targets for faster-acting antidepressants that produce more sustained relief by modulating glutamatergic synaptic strength.

How similar studies have performed: Ketamine's rapid antidepressant effects are well established in prior studies, but applying high-field GluCEST imaging to directly link those effects to glutamatergic synaptic changes in humans is novel and largely untested.

Eligibility criteria

Inclusion Criteria:

1. Age between 25 and 65 years;
2. Current depression as assessed on the SCID;
3. 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
4. Able to comprehend English, as all questionnaires are in this language
5. Ability to provide informed consent Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.

Exclusion Criteria:

1. A sleep disorder other than insomnia, as determined by history;
2. History of bipolar disorder, delirium, dementia, amnestic disorder, schizophrenia and other psychotic disorders as assessed on the SCID;
3. Alcohol or drug abuse in the past year based upon the SCID or urine toxicology screen;
4. 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:

1. Patients with a BMI over 40.
2. Ongoing prescription of 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment;
3. Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression;
4. 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;
5. 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.
6. Current use of Naltrexone;
7. Developmental delay, mental retardation, or intellectual disorder;
8. Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months;
9. Prior participation in another study of ketamine for depression
10. Prior treatment and/or recreational use of ketamine

Where this trial is running

Philadelphia, Pennsylvania

• University of Pennsylvania — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Jennifer R Goldschmied, PhD — University of Pennsylvania
• Study coordinator: Jennifer R Goldschmied, PhD

Conditions Major Depressive Disorder