Clinical TrialTreatment-Resistant Depression (TRD)KetaminePlaceboCompleted

Action of Ketamine in Treatment-Resistant Depression

Randomized, double-blind crossover Phase II–III study (n≈46) comparing IV ketamine (0.5 mg/kg, 40 min) to active control midazolam (30 µg/kg, 40 min) in treatment-resistant major depressive disorder, with escalation to repeated infusion schedules to assess durability.

Target Enrollment
46 participants
Study Type
Phase II/III interventional
Design
Randomized, double Blind

Detailed Description

Randomized double-blind crossover evaluation of a single IV infusion of ketamine (0.5 mg/kg over 40 minutes) versus active control midazolam (30 µg/kg over 40 minutes) in patients with treatment-resistant major depressive disorder; responders may receive repeated infusions to assess durability.

Phase II tests repeated ketamine (3×/week for 2 weeks; 6 infusions) in non-responders to determine whether repeated dosing produces greater and more sustained improvement; Phase III provides weekly ketamine for 4 weeks to responders to evaluate maintenance of effect. Biological assays (BDNF genotype, inflammatory markers, cortisol, melatonin) and clinical scales (MADRS, CGI, QIDS-SR) are collected.

Study Protocol

Preparation

sessions

Dosing

1 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Ketamine

experimental

Intravenous ketamine 0.5 mg/kg infusion (40 min); repeated schedules described in notes.

Interventions

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

    40-minute infusion; phase II: 3 infusions/week ×2 weeks (6 infusions); phase III responders: once weekly ×4 weeks.

Midazolam

active comparator

Active comparator midazolam infusion (30 µg/kg over 40 min).

Interventions

  • Placebo30 µg/kg
    via IV• single dose

    30 µg/kg over 40 minutes (active control midazolam).

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Only participants from the Ottawa area will be considered
  • Provision of written informed consent before initiation of any study-related procedures.
  • Documented primary Axis I clinical diagnosis meeting criteria from the DSM-IV for MDD, as confirmed by the MINI.
  • Failure to respond adequately to at least two antidepressant medication trials and two augmentation strategies (one augmentation may include venlafaxine 225 mg/day or duloxetine 120 mg/day, or a 12-week CBT or interpersonal therapy).
  • MADRS total score ≥ 25 at screening and randomization, with no more than 20% improvement between these two visits.
  • Female subjects of childbearing potential must have a negative urine pregnancy test at enrolment and be willing to use a reliable method of birth control during the study.
  • Abstain from consuming grapefruit juice on the day of the infusions.
  • Be able to understand and comply with study requirements, as judged by the investigator(s).

Exclusion Criteria

  • Subjects with a DSM-IV Axis II disorder that majorly impacts current psychiatric status.
  • Depression secondary to stroke, cancer or other severe medical illnesses.
  • Prior or current substance or alcohol abuse or dependence (except caffeine or nicotine).
  • A positive drug screen.
  • Unwilling to maintain current antidepressant regimen.
  • Unwilling or unable to withhold benzodiazepines or narcotics for required washout periods prior to infusions.
  • Pregnant or lactating, or of childbearing potential and not willing to use approved contraception during the study.
  • Evidence of clinically relevant disease (e.g., renal/hepatic impairment, significant coronary artery disease, cerebrovascular disease, viral hepatitis B/C, AIDS).
  • Unstable clinical findings that would be negatively affected by study medication (e.g., uncontrolled diabetes, hypertension, unstable angina).
  • AST or ALT ≥3× upper normal limit at screening.
  • Uncorrected thyroid disease unless on a stable replacement dose for ≥30 days.
  • Clinically significant laboratory or ECG abnormalities.
  • History of seizure disorder (except febrile convulsions).
  • Subjects judged to require psychotherapy (other than supportive) during the study unless psychotherapy has been ongoing for ≥2 months prior to Visit 2.
  • Known intolerance or hypersensitivity to ketamine or midazolam.
  • Any other condition that would adversely affect participation, per investigator opinion.

Study Details

Locations

Institute of Mental Health Research, Royal Ottawa Hospital — Ottawa, Ontario, Canada

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