Pilot Study: Establishing Glutamatergic Changes in Rapid Antidepressant Effects of Ketamine

NCT06788249 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 857228
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Major Depressive Disorder (MDD)

Outcome Measures

Primary Outcomes (1)

• GluCEST imaging metrics

  relative change in glutamate concentration (% baseline)

  From pre to post-ketamine infusion (2 imaging sessions over a 9-hour span)

Secondary Outcomes (1)

• Hamilton Depression Rating Scale

  From pre to post-ketamine infusion (2 evaluations over a 9-hour span)

Study Arms (1)

Major Depressive Disorder

EXPERIMENTAL

Drug: Ketamine only

Interventions

Ketamine only DRUG

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.

Major Depressive Disorder

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;
• \) 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
• 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

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Jennifer R Goldschmied, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jennifer R Goldschmied, PhD

CONTACT

215-573-2774; jrgolds2@pennmedicine.upenn.edu

Holly Barilla, MS

CONTACT

hbarilla@upenn.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single Group Assignment

Study Record Dates

• First Submitted: January 16, 2025
• First Posted: January 23, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): August 15, 2026
• Study Completion (Estimated): August 15, 2026
• Last Updated: April 21, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)