Glutamatergic Adaptation to Stress as a Mechanism for Anhedonia and Treatment Response With Ketamine

Early Phase 1

Recruiting

• Conditions: Major Depressive Disorder
• Interventions: Other: Placebo; Drug: Ketamine

• Registration Number: NCT05327699
• Lead Sponsor: Emory University

Brief Summary

The main purpose of this study is to investigate the effects of ketamine on decision-making and emotion processing in a sample of individuals diagnosed with Major Depressive Disorder (MDD).

Detailed Description

The main purpose of this study is to understand the effects of sub-anesthetic ketamine doses on varying functional domains of depression such as anhedonia, decision-making, and emotion processing in subjects diagnosed with Major Depressive Disorder (MDD). The study will evaluate these effects using a combination of questionnaires, neuroimaging techniques, and behavioral tasks. The clinical trial portion will only include subjects with MDD (Major Depressive Disorder). A separate group of healthy controls, n=60, will be invited to only complete a behavioral/interview session and one neuroimaging session.The healthy controls group will not be randomized nor receive any study intervention and will only serve to collect performance baseline measures. The primary aims of this study are to evaluate 1) the glutamate stress response in MDD patients and matched controls by whole-brain imaging, 2) the multi-modal associations between glutamate stress response and neuroimaging and behavioral assessments of motivation and valuation, and 3) the effect of ketamine versus placebo on glutamate stress response in MDD subjects.

Study Timeline

• Study First Submitted: 2022-04-07
• Study First Submitted QC: 2022-04-07
• Study First Posted: 2022-04-14
• Study Start: 2022-11-08
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-18
• Last Update Posted: 2025-04-20
• Primary Completion: 2026-11-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 140

Inclusion Criteria

MDD Patients:

• willing and able to give written informed consent
• men or women, 18-65 years of age
• primary diagnosis of DSM-V MDD, current, as diagnosed by the SCID-I
• score of ≥20 on the Beck Depression Inventory, which will include patients characterized as having "moderate/severe" (20-28) or "very-severe" (29-63) depressive symptoms
• off all antidepressant therapy for at least 8 weeks prior to the baseline visit

Healthy Controls:

• willing and able to give written informed consent
• men or women, 18-65 years of age

Exclusion Criteria

MDD Patients:

• history of any bipolar disorder or psychotic disorder
• active psychotic symptoms of any type
• substance abuse/dependence within 6 months of study entry (as determined by SCID)
• unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination and laboratory testing), including upper respiratory disease or asthma, glaucoma or porphyria.
• active suicidal ideation as determined by a score ≥3 on the Columbia Suicide Severity Rating Scale (C-SSR)
• use of any recreational drugs as confirmed by urine drug screen at the time of scanning
• pregnancy or lactation
• use of glucocorticoids at any time during the study
• Raynaud's disease that may interfere with the cold-pressor
• contraindications for MRI
• MMSE score <28
• elevated blood pressure prior to infusion (systolic > 160 or diastolic >100)
• history of treatment resistance as determined by ATRQ
• prior adverse reaction to ketamine
• use of antipsychotic medications
• use of greater than 2mg daily of lorazepam or similar benzodiazipine.
• Regular smoker as self-reported

Healthy Controls:

• evidence of any psychiatric disorder with exception of specific phobia, and no history of any psychiatric disorder except mild past substance use disorder as diagnosed by the SCID-I
• history of any substance abuse within the last 6 months
• use of any recreational drugs as confirmed by urine drug screen at the time of scanning
• pregnancy or lactation
• use of glucocorticoids at any time during the study
• Raynaud's disease that may interfere with the cold-pressor
• contraindications for MRI
• MMSE score <28
• Regular smoker as self-reported

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Major depressive disorder (MDD) Placebo	Placebo	Participants randomized to the placebo arm will receive a single intravenous (IV) infusion of saline through an indwelling catheter over a 40-100min period.
Major depressive disorder (MDD) Ketamine	Ketamine	Participants randomized to the ketamine arm will receive a single intravenous (IV) infusion of ketamine at 0.5mg/kg through an indwelling catheter over a 40-100min period.

Primary Outcome Measures

Name	Time	Method
Change in glutamate concentration in the medial prefrontal cortex (mPFC)	Baseline, 24 hours post-infusion, 14 days post-infusion	The glutamate concentration in the mPFC as determined by in vivo magnetic resonance spectroscopy (MRS) at a field strength of 3 Tesla (3T) using standard MRS protocols. The levels of glutamate metabolite will be quantified using a custom quantification algorithm for modelling the background noise inherent in NMR (Nuclear Magnetic Resonance) signals. In MDD participants receiving ketamine, acute stress challenges will result in decreased glutamate in mPFC at 24 hrs that will be sustained at 2 weeks.

Trial Locations

Locations (1)

Emory University; 🇺🇸 Atlanta, Georgia, United States