Clinical TrialTreatment-Resistant Depression (TRD)KetaminePlaceboRecruiting

Predictors of Intravenous Ketamine Response in TRD

Randomized, double-blinded, midazolam-controlled crossover trial (n=40) testing single IV ketamine (0.5 mg/kg over 40 minutes) versus midazolam (30 µg/kg) in treatment-resistant depression to identify predictors of rapid and sustained response.

Target Enrollment
40 participants
Study Type
Phase III interventional
Design
Randomized, quadruple Blind

Detailed Description

This randomized, double-blind, midazolam-controlled crossover study will recruit 40 participants with treatment-resistant depression to identify clinical, behavioural, and neurophysiological predictors of response to a single infusion of IV ketamine (0.5 mg/kg over 40 minutes).

Participants receive two infusions 21 days apart (ketamine and midazolam in counterbalanced order). Outcomes include MADRS at 24 hours, 7 and 14 days, weekly self-report (QIDS-SR16), measures of anhedonia (SHAPS, DARS, PVSS-21), actigraphy, EEG, speech sampling, and computerized tasks to build predictive models of rapid and sustained antidepressant response.

The trial uses midazolam as an active psychoactive comparator to improve blinding; safety measures and medication restrictions (e.g., grapefruit juice, benzodiazepines) are in place to reduce interaction risks.

Study Protocol

Preparation

sessions

Dosing

2 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Ketamine

experimental

IV ketamine 0.5 mg/kg over 40 minutes; crossover with midazolam comparator.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single dose

    Infusion 0.5 mg/kg over 40 minutes; one infusion per treatment period.

Midazolam

active comparator

IV midazolam 30 µg/kg over 40 minutes as active comparator to preserve blinding.

Interventions

  • Placebo30 µg/kg
    via IV• single dose

    Midazolam 30 µg/kg over 40 minutes (encoded as active comparator in notes).

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Able to fluently read in English with or without optical correction
  • Ability to understand and comply with the study requirements (determined by investigators)
  • Provision of written informed consent
  • Documented diagnosis of MDD or bipolar disorder meeting DSM-5 criteria, currently in a single or recurrent episode without psychotic features (confirmed by Diagnostic Assessment Research Tool)
  • Failure of at least two antidepressant medications from different pharmacological classes, and at least one augmentation agent, each given at adequate doses for ≥6 weeks (recorded using the Antidepressant Treatment History Form - Short Form). Augmentation strategies may include therapies listed in CANMAT guidelines, including a 12-week course of CBT or interpersonal therapy.
  • MADRS score ≥25 at initial assessment and Day -1, and ≤20% improvement between those visits
  • For sexually active premenopausal females: negative urine pregnancy test at enrolment and commitment to an appropriate birth control method for study duration
  • Abstain from grapefruit juice on day of infusion and from benzodiazepines within 24 hours of infusion
  • Adherence to maintaining current antidepressant management

Exclusion Criteria

  • Exclusion Criteria:
  • Pregnant or breastfeeding
  • Allergies to ketamine or midazolam
  • Concomitant use of medications with potential for clinically significant interactions with ketamine or midazolam (e.g., MAO inhibitors, methylene blue)
  • Concomitant use of naltrexone or narcotics; positive urine drug screen or history of DSM-5 substance use disorder (except caffeine or nicotine); previous or current benzodiazepine abuse
  • Previous ketamine use (therapeutic or recreational)
  • History of electroconvulsive therapy or comorbid DSM-5 personality disorder with major impact on mental status
  • Secondary depressive disorders (e.g., secondary to stroke, cancer, other somatic pathology)
  • Subjects starting psychotherapy during the trial or who started psychotherapy within 2 months of trial
  • Medical exclusions: epilepsy; current or historical renal disease; clinically significant hepatic disease or liver enzymes (AST, ALT) ≥3× upper limit; myocardial infarct within 1 year; COPD; untreated obstructive sleep apnoea; cerebrovascular disease; intracerebral structural lesions; viral hepatitis B or C; AIDS; interstitial cystitis; glaucoma; uncontrolled hypertension; decompensated heart failure; current uncorrected thyroid pathology or recent correction within 30 days; any unstable somatic pathology or clinically significant investigational abnormality (biochemical, ECG) that would be adversely impacted by study procedures or impact procedures

Study Details

Locations

Mood Disorders Program — Halifax, Nova Scotia, Canada

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