Clinical TrialParallelTreatment-Resistant Depression (TRD)KetamineKetamineKetamineCompleted

Effectiveness of ketamine therapy among patients with treatment-resistant depression: a double-blind, randomised, controlled trial

This double-blind, randomised, controlled trial (n=183), known as the Ketamine for Adult Depression Study (KADS), explored the effectiveness of ketamine therapy in treating patients with treatment-resistant depression (TRD).

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Target Enrollment
183 participants
Study Type
Phase III interventional
Design
Randomized, double Blind

Detailed Description

Randomised, double-blind RCT phase: subcutaneous ketamine (100 mg/mL) given twice weekly for 4 weeks; participants screened 1 month after RCT for eligibility to enter a 4-week open-label extension after a 1-month break.

Dosing is weight-based by volume (0.22–0.53 mL starting volumes depending on body weight) with the possibility of dose increases up to 0.91 mL; adherence ensured by staff-administered injections. Primary outcome: remission at end of RCT phase (MADRS <10); MADRS change also assessed.

Study Protocol

Preparation

sessions

Dosing

8 sessions

Integration

sessions

Study Arms & Interventions

Ketamine (combined KADS cohorts)

experimental

Generic KADS ketamine arm used for papers that report combined-cohort ketamine analyses.

Interventions

  • Ketamine0.5 - 0.9 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous racemic ketamine; fixed-dose cohort used 0.5 mg/kg and flexible-dose cohort escalated 0.5-0.9 mg/kg.

Midazolam (combined KADS cohorts)

active comparator

Generic KADS active-control arm used for papers that report combined-cohort midazolam analyses.

Interventions

  • Compound0.025 - 0.045 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous midazolam active control; fixed-dose cohort used 0.025 mg/kg and flexible-dose cohort escalated 0.025-0.045 mg/kg.

Fixed-dose ketamine 0.5 mg/kg

experimental

KADS cohort 1 fixed-dose subcutaneous racemic ketamine.

Interventions

  • Ketamine0.5 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous injection.

Fixed-dose midazolam 0.025 mg/kg

active comparator

KADS cohort 1 fixed-dose subcutaneous midazolam active control.

Interventions

  • Compound0.025 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous injection active control.

Flexible-dose ketamine 0.5-0.9 mg/kg

experimental

KADS cohort 2 response-guided flexible-dose subcutaneous racemic ketamine.

Interventions

  • Ketamine0.5 - 0.9 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous injection; escalation steps 0.6, 0.75, and 0.9 mg/kg if not improved by 50%.

Flexible-dose midazolam 0.025-0.045 mg/kg

active comparator

KADS cohort 2 response-guided flexible-dose subcutaneous midazolam active control.

Interventions

  • Compound0.025 - 0.045 mg/kg
    via Other• twice weekly for 4 weeks• 8 doses total

    Subcutaneous active control; escalation steps matched ketamine injection volumes.

Participants

Ages
18 – 99
Sexes
Male & Female

Inclusion Criteria

  • Criteria assessed by the research team include:
  • Major Depressive Disorder (MDD) for at least 3 months.
  • An inadequate response to at least 2 adequate antidepressant courses; stable dose of antidepressant medications at least 4 weeks prior to trial entry.
  • Montgomery Åsberg Depression Rating Scale (MADRS) score of at least 20.

Exclusion Criteria

  • Criteria assessed by the research team to determine suitability include:
  • Psychotic disorder.
  • Bipolar disorder.
  • Medical and neurologic conditions.
  • Psychiatric disorders other than MDD.
  • Planned major changes to psychotropic medication.
  • Planned or probable use of ECT.
  • Risk of suicide.
  • Substance use, abuse, dependence.
  • Recent or planned ketamine treatment.
  • Medical conditions in which use of ketamine or sedating medications may pose a significant health risk.
  • Women of childbearing potential not taking reliable contraception.
  • Inability to complete the trial.

Study Details

Study Team

Sponsors & Collaborators

Locations

Unknown facility — Australia

Related Publications

Open AccessindividualPrimary

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial

In this phase 3 randomised double‑blind trial, adequately dosed subcutaneous racemic ketamine given twice weekly for 4 weeks produced significantly higher remission than midazolam in the flexible‑dose cohort (19.6% v. 2.0%; OR 12.1, 95% CI 2.1–69.2, P = 0.005) but not in the fixed‑dose cohort. Ketamine was well tolerated with transient adverse effects resolving within two hours, supporting the subcutaneous route as a practical option for treatment‑resistant depression.

Published
Journal
British Journal of Psychiatry
Authors
Loo, C., Glozier, N., Barton, D., Baune, B. T., Mills, N. T., Fitzgerald, P., Glue, P., Sarma, S., Galvez-Ortiz, V., Hadzi-Pavlovic, D., Alonzo, A., Dong, V., Martin, D., Nikolin, S., Mitchell, P. B., Berk, M., Carter, G., Hackett, M., Leyden, J., Hood, S., Somogyi, A. A., Lapidus, K., Stratton, E., Gainsford, K., Garg, D., Thornton, N. L. R., Fourrier, C., Richardson, K., Rozakis, D., Scaria, A., Mihalopoulos, C., Chatterton, M. L., McDonald, W. M., Boyce, P., Holtzheimer, P. E., Kozel, F. A., Riva-Posse, P., Rodgers, A.
Open AccessindividualSecondary analysis

Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study

In this secondary analysis of a multisite, double-blind RCT (n=174) in treatment‑resistant depression, subcutaneous racemic ketamine given twice weekly for 4 weeks at flexible, response‑guided doses (35-63mg/70kg) produced a significant short‑term reduction in anxiety (HAM‑A) versus midazolam, whereas a fixed low dose (35mg/70kg) did not. The anxiolytic effect was mediated by antidepressant response and was not maintained 4 weeks after the end of treatment.

Published
Journal
British Journal of Psychiatry
Authors
Mills, N. T., Nikolin, S., Glozier, N., Barton, D., Baune, B. T., Fitzgerald, P. B., Glue, P., Sarma, S., Rodgers, A., Hadzi-Pavlovic, D., Alonzo, A., Dong, V., Martin, D., Mitchell, P. B., Berk, M., Carter, G., Hackett, L., Somogyi, A. A., Mihalopoulos, C., Chatterton, M. L., Hood, S., Loo, C. K.
PaywallindividualSecondary analysis

Economic evaluation of subcutaneous ketamine injections for treatment resistant depression: A randomised, double-blind, active-controlled trial - The KADS study

This cost-utility analysis, alongside a randomised controlled trial (n=174), compared subcutaneous ketamine (twice-weekly for 4 weeks) with midazolam in treatment-resistant depression. Including midazolam costs, ketamine raised QALYs (0.435 vs 0.352) and was dominant with an 89-91 % chance of costing < $50 000/QALY, but once these comparator costs were excluded ketamine was no longer cost-effective (ICER ≈ $108 500-$251 250/QALY, ≤ 5 % probability).

Published
Journal
Journal of Affective Disorders
Authors
Chatterton, M. L., Perez, J. K., Thai, T., Faller, J., Loo, C. K., Glozier, N., Barton, D., Baune, B. T., Mills, N. T., Fitzgerald, P. B., Glue, P., Sarma, S., Hadzi-Pavlovic, D., Dong, V., Martin, D., Mitchell, P. B., Berk, M., Carter, G., Hackett, M., Hood, S., Somogyi, A. A., Rodgers, A., Mihalopoulos, C.