Clinical TrialTreatment-Resistant Depression (TRD)KetamineKetaminePlaceboCompleted

Efficacy of Repeated Ketamine Infusions for Treatment-resistant Depression

Randomised, parallel RCT (n=62) in Veterans with treatment‑resistant depression comparing six IV ketamine infusions (0.5 mg/kg) over 12 days versus a single IV ketamine infusion (0.5 mg/kg) preceded by five midazolam infusions (0.045 mg/kg) as an active comparator.

Target Enrollment
62 participants
Study Type
Phase II interventional
Design
Randomized, triple Blind

Detailed Description

This single‑centre, randomised, triple‑masked trial tested whether six serial IV ketamine infusions (0.5 mg/kg) are superior to a single ketamine infusion preceded by five midazolam infusions (0.045 mg/kg) for reducing depressive symptoms in Veterans with treatment‑resistant depression.

Primary outcome was MADRS score 24 hours after the last infusion. Infusions were delivered Monday‑Wednesday‑Friday over a 12‑day infusion phase; follow‑up visits occurred weekly for 4 weeks, then fortnightly for 8 weeks, then monthly until 24 weeks or relapse.

Study Protocol

Preparation

sessions

Dosing

6 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Six ketamine infusions

experimental

Six IV ketamine infusions (0.5 mg/kg) over two weeks (M-W-F schedule).

Interventions

  • Ketamine0.5 mg/kg
    via IV• six infusions over 12 days• 6 doses total

    Infusions on days 1,3,5,8,10,12; each infusion over 40 minutes.

Single ketamine + midazolam

active comparator

Single IV ketamine infusion (0.5 mg/kg) preceded by five midazolam infusions (0.045 mg/kg) as active comparator; same schedule.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single infusion• 1 doses total

    Single ketamine infusion administered on final infusion day; infusion over 40 minutes.

  • Placebo0.045 mg/kg
    via IV• five infusions over 12 days• 5 doses total

    Midazolam 0.045 mg/kg given on days 1,3,5,8,10 as active comparator.

Participants

Ages
18 – 75
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Male or female Veterans aged 18 to 75 years.
  • Have a telephone in their home and able to hear telephone conversations.
  • Must meet current DSM-IV criteria for major depressive disorder (MDD), single or recurrent, without psychotic features confirmed by SCID depression subset.
  • Have score ≥32 on the Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30) at screening.
  • Current major depressive episode resistant to treatment defined as failure to achieve improvement from at least 2 antidepressant trials of different pharmacological classes (assessed by ATHF).
  • If applicable, current antidepressant dosages including augmenting agents and/or frequency and duration of psychotherapy must remain stable for at least 6 weeks prior to study start.

Exclusion Criteria

  • Exclusion Criteria:
  • Inability to speak English or provide written informed consent.
  • Moderate/severe cognitive impairment (MMSE ≤27).
  • Current or lifetime DSM criteria for PTSD, acute stress disorder, psychosis-related disorder, bipolar I or II disorder, substance-induced mood disorder, any mood disorder due to a general medical condition or any Axis I disorder other than MDD as the primary presenting problem.
  • History of moderate or severe traumatic brain injury, Parkinson's disease, dementia, multiple sclerosis, seizures or other CNS disorders.
  • Substance use disorder within 6 months or positive urine toxicology at baseline.
  • Clinically unstable medical illness that could compromise ability to tolerate procedures (e.g., recent myocardial ischemia/arrhythmias, CHF, severe pulmonary/renal/hepatic disease, uncontrolled hypertension).
  • Current or within 14 days use of barbiturates or MAO inhibitors.
  • For women: pregnancy, initiation of hormonal treatments within 3 months, or inability/unwillingness to use medically accepted contraception during study.
  • Imminent risk of suicidal/homicidal ideation and/or behaviour with intent and/or plan.

Study Details

Locations

Minneapolis VA Health Care System, Minneapolis, MN — Minneapolis, Minnesota, United States

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