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

Emory University

Status and phase: Enrolling; Early Phase 1

Conditions: Major Depressive Disorder

Treatments: Drug: Ketamine; Other: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05327699

STUDY00003476

R01MH126083-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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).

Full 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.

Enrollment: 140 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

MDD Patients:

• willing and able to give written informed consent
• men or women,18-65 years of age
• primary diagnosis of DSM (Diagnostic and Statistical Manual of Mental Disorders)-V MDD, current, as diagnosed by the SCID-I (Structured Clinical Interview for DSM Disorders)
• 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)
• 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 (Mini-Mental State Exam) score <28
• elevated blood pressure prior to infusion (systolic > 160 or diastolic >100)
• history of treatment resistance as determined by ATRQ (Antidepressant Treatment Response Questionnaire)
• prior adverse reaction to ketamine
• use of antipsychotic medications
• use of greater than 2mg daily of lorazepam or similar benzodiazipine

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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140 participants in 3 patient groups, including a placebo group

Major depressive disorder (MDD) Ketamine

Experimental group

Description:

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.

Treatment:

Drug: Ketamine

Major depressive disorder (MDD) Placebo

Placebo Comparator group

Description:

Participants randomized to the placebo arm will receive a single intravenous (IV) infusion of saline through an indwelling catheter over a 40-100min period.

Treatment:

Other: Placebo

Healthy Controls

No Intervention group

Description:

The subjects in this group will not receive any intervention.