Neural Circuit Effects of Ketamine in Depression

Neural Circuit-Specific Mechanisms of Ketamine's Effect on Anhedonia and Anxiety in Depression Using Ultra-High Field 7-Tesla MRI

This project is designed to examine the role of the subgenual anterior cingulate cortex (sgACC) in anhedonia and anxiety in humans with depression, as well as the acute and sustained effects of ketamine on agACC activation and depression symptoms.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Ketamine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sibilla Masieri; Email: sibilla.masieri@mssm.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • ICAHN School of Medicine at Mount Sinai
      • Principal Investigator: James Murrough, MD, PhD
      • Contact: Sibilla Masieri; Email: Sibilla.Masieri@mssm.edu,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

MDD Group

• Male or female aged 18-65 years;
• Ability for participant to comply with the requirements of the study as determined by the PI;
• Capacity to provide informed consent;
• Meets diagnostic criteria for current MDD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5);
• In a current major depressive episode (MDE) of at least moderate severity according to DSM-5;
• Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year).
• Women of childbearing potential must have a negative pregnancy test at screening and prior to the infusion.

HC Group

• Male or female aged 18-65 years;
• Capacity to provide informed consent;
• Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year).
• Ability for participant to comply with the requirements of the study as determined by the PI;

Exclusion Criteria:

MDD Group

• Current or history of schizophrenia or other psychotic disorder/episode, bipolar disorder, neurodevelopmental disorder, or neurocognitive disorder;
• Current major depressive disorder with psychotic features;
• Substance use disorder within the past 2 years*;
• Lifetime history of ketamine use disorder;
• Antidepressant medication within 2 weeks of Baseline (4 weeks for fluoxetine);
• Severe current illness as reflected by a CGI score >5;
• Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
• Clinically significant abnormalities of laboratories, physical examination, or ECG;
• Positive urine toxicology screen for drugs of abuse at the time of screening, except cannabis;
• Women who plan to become pregnant, are pregnant or are breast-feeding (because the medical risk of using ketamine during pregnancy and breast-feeding is unknown);
• Active suicidal intent or plan; CSSRS score >2;
• Any contraindications to MRI, including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more;
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the participant or the quality of the data.

HC Group

• Current or history of any psychiatric, neurodevelopmental disorder, or neurocognitive disorder;
• Substance use disorder within the past 2 years*;
• Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
• Clinically significant abnormalities of laboratories or physical examination;
• Positive urine toxicology screen for drugs of abuse at the time of screening, except cannabis;
• Current pregnancy;
• Women who are breast feeding;
• Active suicidal intent or plan; CSSRS score >2;
• Any contraindications to MRI, including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine; Participants in the ketamine arm will receive a single infusion of ketamine	Drug: Ketamine; 0.5 mg/kg ketamine dissolved in 100 mL saline, delivered intravenously
Placebo Comparator: Placebo; Participants in the placebo arm will receive a single placebo infusion of normal saline	Drug: Placebo; Normal saline delivered intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sgACC response to the Incentive Flanker Task	Subgenual anterior cingulate cortex (sgACC) response to reward measured by the BOLD (Blood Oxygen Level Dependent) signal within the sgACC region of the brain, during an fMRI Incentive Flanker Task in healthy controls and in adults with MDD. BOLD signal is the unit of measure of this outcome.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-related change in sgACC response to the Incentive Flanker Task	Treatment-related change from baseline to 1-day post treatment in subgenual anterior cingulate cortex (sgACC) response to reward measured by the BOLD (Blood Oxygen Level Dependent) signal within the sgACC region of the brain, during an fMRI Incentive Flanker Task. MDD adults only.	Baseline and Day 1

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: James Murrough, MD/PhD, ICAHN School of Medicine at Mount Sinai; Principal Investigator: Laurel Morris, ICAHN School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Estimated): March 30, 2028
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: January 9, 2024
• First Posted (Actual): January 19, 2024

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics; Neurotransmitter Agents; Anesthetics, Intravenous; Anesthetics, General; Excitatory Amino Acid Agents; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists; Ketamine
• Other Study ID Numbers: GCO 22-1619; R01MH134045 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Immediately following publication. No end date.

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ('learned intermediary') identified for this purpose.

Any purpose. Specify Other Mechanism Data from this study will be submitted to the National Institute of Mental Health Data Archive (NDA). The NDA is a data repository run by the National Institute of Mental Health (NIMH) that facilitates data sharing across mental health and other research communities. Periodically during and after study completion, the researchers will upload deidentified data information to the NDA. Other researchers nationwide can then file an application to obtain access to deidentified study data for research purposes.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No