Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine

NCT04977674 | Completed Early Phase 1

• 1 other identifier: MR/T028084/1
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching aim of this research is to determine the acute effects of ketamine on brain glutamate, functional connectivity and cerebral blood flow in treatment-resistant depression, explore whether the effects are attenuated by the opioid receptor antagonist naltrexone and relate these findings to antidepressant response.

Conditions

Depressive Disorder, Treatment-Resistant

Keywords

ketamine; naltrexone; glutamate; opioid; major depressive disorder; MDD

Outcome Measures

Primary Outcomes (1)

• Change in Glutamate

  Compare changes in glutamate and GLX (glutamate +glutamine), referenced to total creatine (tCr), during ketamine infusion as measured by functional magnetic resonance spectroscopy (1H-fMRS) for naltrexone versus placebo pre-treatment conditions. Hypothesis: There will be a significant increase in glutamate measures during ketamine administration compared to a resting baseline condition in a medial prefrontal cortex (mPFC) /anterior cingulate cortex (ACC) region. Pre-treatment with naltrexone will attenuate this increase.

  Changes will be in the same session comparing the ketamine infusion period to the pre-ketamine infusion baseline

Secondary Outcomes (2)

• Change in Resting State Functional Connectivity

  Changes will be in the same session comparing post-infusion (immediately after ketamine infusion) to the pre-ketamine infusion baseline

• Change in Cerebral Blood Flow

  Changes will be in the same session comparing data collected 30 minutes after the ketamine infusion commences to the pre-ketamine infusion baseline

Study Arms (2)

A: Visit 1) Naltrexone + Ketamine, Visit 2) Placebo + Ketamine

EXPERIMENTAL

Participants randomly assigned to arm A: VISIT 1) Naltrexone 50mg before the administration of ketamine 0.5mg/kg. VISIT 2) Placebo before the administration of ketamine 0.5mg/kg. Study visits are separated by 14-28 days.

Drug: Naltrexone; Drug: Placebo; Drug: Ketamine

B: Visit 1) Placebo + Ketamine, Visit 2) Naltrexone + Ketamine

EXPERIMENTAL

Participants randomly assigned to arm B: VISIT 1) Placebo before the administration of ketamine 0.5mg/kg. VISIT 2) Naltrexone 50mg before the administration of ketamine 0.5mg/kg. Study visits are separated by 14-28 days.

Drug: Naltrexone; Drug: Placebo; Drug: Ketamine

Interventions

Naltrexone DRUG

Pre-treatment with naltrexone 45 min before the ketamine infusion.

A: Visit 1) Naltrexone + Ketamine, Visit 2) Placebo + Ketamine; B: Visit 1) Placebo + Ketamine, Visit 2) Naltrexone + Ketamine

Placebo DRUG

Pre-treatment with placebo 45 min before the ketamine infusion.

A: Visit 1) Naltrexone + Ketamine, Visit 2) Placebo + Ketamine; B: Visit 1) Placebo + Ketamine, Visit 2) Naltrexone + Ketamine

Ketamine DRUG

Participants receive intravenous ketamine infusion (0.5 mg/kg over 40 min) at both study visits.

A: Visit 1) Naltrexone + Ketamine, Visit 2) Placebo + Ketamine; B: Visit 1) Placebo + Ketamine, Visit 2) Naltrexone + Ketamine

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Right-handed participants between the ages of 18 and 50 years inclusive.
• Able to provide informed written consent
• Fulfil Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (DSM-5) criteria for a primary diagnosis of current single or recurrent episodes of MDD of at least moderate severity but without psychotic features as defined on the MINI 7.0. Positive and primary diagnoses on the MINI 7.0 will be subject to confirmation at clinical interview by a psychiatrist.
• item HAM-D score ≥ 18.
• Have failed to respond to 2 or more antidepressants prescribed at minimum effective dose for at least 6 weeks OR at least 1 antidepressant prescribed at the minimum effective dose for at least 6 weeks AND a course of evidence-based psychotherapy given for at least 6 sessions.
• The subject is off all drugs likely to interact with glutamate or opioid system at least 14 days before starting the study (antipsychotics, anticonvulsants, mood stabilisers, gabapentinoids, opiates, opioid agonists/antagonists/combinations and stimulants). There are two exceptions. The first is any regular antidepressant(s) the subject may be taking (apart from MAOIs that are not permitted). Second, is short acting benzodiazepines or hypnotics for distressing anxiety or insomnia (up to 72 hours prior to each MRI scan).
• The subject has a resting pulse ≥51 bpm and ≤100 bpm at the screening visit. For subjects in good physical condition, the lower limit is ≥45 bpm.
• The subject has a resting systolic blood pressure ≥91 mmHg and ≤140 mmHg and a resting diastolic blood pressure ≥51 mmHg and ≤90 mmHg at the screening visit. An out-of-range resting systolic blood pressure may be repeated once if a medically valid reason is present, for example, the subject suffers from white-coat hypertension or has just come from low outdoor temperatures or experienced stress (e.g. late arrival). The medically valid reason must be documented and signed by the investigator.
• Body Mass Index (BMI) of 18 to 30 kg/m2 inclusive and a total body weight 50-100 kg at the screening visit.
• Able to attend interviews and tolerate MRI scanning procedures.

You may not qualify if:

• Diagnosis of bipolar disorder or psychotic disorder on the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
• A first-degree relative with bipolar disorder, schizoaffective disorder, or schizophrenia, with the potential participant younger than 33 years (ie, still at age of risk for a psychotic disorder).
• Personal history of a ≥ 1 suicide attempt in the past year, or active ideation with plan and intent defined using the C- SSRS ("Suicidal Behaviour" section and question 5) alongside confirmation at clinical interview with a psychiatrist.
• Diagnosis of drug or alcohol dependence syndrome (defined as meeting DSM-5 criteria for any dependence syndrome) on the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
• History of IV drug use.
• Current recreational use of ketamine.
• A positive urine drug screen on or after the screening visit during their active involvement in the study for ketamine, opiates, methadone, cocaine, amphetamines, benzodiazepines or cannabinoids.
• History of nonresponse or intolerance to ketamine.
• Significant uncontrolled physical illness particularly if it may affect the brain or glutamatergic system (blood dyscrasias, lymphomas, hypersplenism, endocrinopathies, renal failure or severe chronic obstructive lung disease, autonomic neuropathies and active malignancy).
• Significant history of cardiovascular or cerebrovascular illness which may compromise the safety of ketamine use (myocardial infarction, heart failure, valvulopathy, stroke or transient ischaemic attack). Subjects with allergies and sensitivities to ketamine or similar compounds will also be excluded.
• Inability to provide a screening blood sample, urine sample or electrocardiogram.
• Electrocardiographic abnormalities, defined as any abnormality that is not normal sinus rhythm and determined as clinically significant by a medical doctor.
• Women of childbearing potential not using adequate contraception.
• Pregnant or breast-feeding women.
• Any previous neurosurgery or neurological disorder, including epilepsy

Sponsors & Collaborators

• King's College London: lead

Study Sites (1)

King's College London

London, SE58AF, United Kingdom

Location

Related Publications (1)

• Jelen LA, Lythgoe DJ, Stone JM, Young AH, Mehta MA. Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nat Med. 2025 Sep;31(9):2958-2966. doi: 10.1038/s41591-025-03800-w. Epub 2025 Jul 24.

  PMID: 40707608 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Interventions

Naltrexone; Ketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2021
• First Posted: July 27, 2021
• Study Start: September 27, 2021
• Primary Completion: February 13, 2023
• Study Completion: February 20, 2023
• Last Updated: March 2, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)