Glutamate and Opioid Mechanisms of Antidepressant... — Clinical Trial Details

This randomised, double-blind, quadruple-masked crossover study examines the acute neurobiological effects of intravenous ketamine (0.5 mg/kg over 40 minutes) on brain glutamate, functional connectivity and cerebral blood flow in adults with treatment-resistant depression. Each participant undergoes two imaging sessions receiving ketamine after oral naltrexone 50 mg or matched placebo administered 45 minutes prior.

Primary aims are to determine whether naltrexone attenuates ketamine-induced glutamatergic and imaging changes and whether these neurobiological measures relate to antidepressant response; outcomes include imaging-based glutamate measures, functional connectivity, CBF, clinical rating scales and safety/tolerability.

Participants

Ages

18 – 50

Sexes

Male & Female

BMI

18 - 30

Psychosis History

Excluded

Inclusion Criteria

Right-handed participants between the ages of 18 and 50 years inclusive.
Able to provide informed written consent.
Fulfil DSM-5 criteria for a primary diagnosis of current single or recurrent episodes of MDD of at least moderate severity without psychotic features as defined on the MINI 7.0, confirmed by clinical interview.
17-item HAM-D score ≥18.
Failed to respond to 2 or more antidepressants at minimum effective dose for ≥6 weeks OR at least 1 antidepressant at minimum effective dose for ≥6 weeks plus a course of evidence-based psychotherapy of ≥6 sessions.
Off drugs likely to interact with glutamate or opioid systems for at least 14 days prior to study (exceptions: regular antidepressants except MAOIs; short-acting benzodiazepines/hypnotics up to 72 hours prior to each MRI).
Resting pulse ≥51 bpm and ≤100 bpm at screening (≥45 bpm for subjects in good physical condition).
Resting systolic BP ≥91 mmHg and ≤140 mmHg and diastolic BP ≥51 mmHg and ≤90 mmHg at screening (one repeat allowed if medically justified).
BMI 18–30 kg/m2 and body weight 50–100 kg at screening.
Able to attend interviews and tolerate MRI procedures.

Exclusion Criteria

Diagnosis of bipolar disorder or psychotic disorder on MINI 7.0.
First-degree relative with bipolar disorder, schizoaffective disorder, or schizophrenia if participant is younger than 33 years.
Personal history of ≥1 suicide attempt in the past year, or active ideation with plan and intent as defined by the C-SSRS.
Diagnosis of drug or alcohol dependence syndrome on MINI 7.0.
History of IV drug use or current recreational ketamine use.
Positive urine drug screen for ketamine, opiates, methadone, cocaine, amphetamines, benzodiazepines or cannabinoids on or after screening.
History of nonresponse or intolerance to ketamine.
Significant uncontrolled physical illness affecting brain or glutamatergic system.
Significant cardiovascular or cerebrovascular disease or allergy/sensitivity to ketamine.
Inability to provide required blood/urine samples or ECG; clinically significant biochemical or ECG abnormalities.
Women of childbearing potential not using adequate contraception; pregnant or breastfeeding women.
Previous neurosurgery, neurological disorder (including epilepsy), head injury with ≥1 hour unconsciousness; any contraindication to MRI.
Use of compounds affected by ketamine (diazepam, warfarin, carbamazepine, phenytoin, theophylline, levothyroxine).
Unwilling/unable to comply with lifestyle guidelines.
Exclusion from analysis: excessive head motion on resting state scan (Framewise displacement of 0.5 mm on >20% of scans); images failing QC; side effects during scan impacting interpretability (e.g. nausea).

Company

Product

Legal

Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine

Detailed Description

Study Protocol

Preparation

Locations

Dosing

Integration

Study Arms & Interventions

Naltrexone vs Placebo + Ketamine

Interventions

Participants

Inclusion Criteria

Exclusion Criteria

Study Details

Study Team

Sponsors & Collaborators