Ketamine As an Adjunctive Therapy for Major Depression (2)

NCT04939649 | Completed Phase 3 DMC

• 2 other identifiers: CRFSPN0042019-003109-92
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

Pragmatic, randomised, controlled, parallel-group, superiority trial of ketamine vs. midazolam as an adjunctive therapy for depression. The main purpose of the trial is to assess the mood-rating score difference between ketamine and midazolam from before the first infusion to 24 hours after the final infusion, supplemented by a 95% confidence interval. There will also be a 24-week follow-up after the final infusion session.

Conditions

Major Depressive Episode; Unipolar Depression; Bipolar Depression

Keywords

ketamine; glutamate

Outcome Measures

Primary Outcomes (1)

• Montgomery Asberg Depression Rating Scale-10 item version (MADRS)

  The MADRS is a validated, 10-item, observer-rated scale that measures the symptoms and severity of depression. The primary outcome measure will be the change from baseline in the MADRS score to 24 hours after the final infusion. MADRS will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±20) mins before the infusion begins; +60 (±10) mins and +120 (±10) mins after the infusion begins; +24 (±1) hours after the infusion ends) and at the 6, 12 and 24 weeks follow-up time points. Sleep and appetite scores will be carried over from -40 minutes to +60 minutes, +120 minutes, and 24 hours after each infusion. Response to treatment is defined as a ≥50% improvement from baseline MADRS score. Remission is defined as achieving a MADRS score ≤10. For those deemed to be treatment remitters, relapse at follow-up time points is defined as a MADRS score of ≥18.

  28 weeks

Secondary Outcomes (12)

• The Clinician-Administered Dissociative States Scale (CADSS)

  4 weeks

• The Brief Psychiatric Rating Scale (BPRS)

  4 weeks

• Young Mania Rating Scale (YMRS; mood item)

  4 week

• Observer's Assessment of Alertness/Sedation; responsiveness subscale (OAA/S-R)

  4 weeks

• 20-item Physician Withdrawal Checklist (PWC-20)

  16 weeks

Study Arms (2)

Ketamine

EXPERIMENTAL

Participants will receive up to a four-week course of twice-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.

Drug: Ketamine

Midazolam

ACTIVE COMPARATOR

Participants will receive up to a four-week course of twice-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.

Drug: Midazolam

Interventions

Ketamine DRUG

A sub-anaesthetic dose of ketamine will be administered for up to a four-week course of twice-weekly infusions.

Also known as: Ketalar

Ketamine

Midazolam DRUG

A sub-anaesthetic dose of midazolam will be administered for up to a four-week course of twice-weekly infusions.

Also known as: Hypnovel

Midazolam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years old.
• Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 20 at screening and start of the first infusion.
• Voluntary admission for treatment of an acute depressive episode
• Meet DSM-5 criteria for a major depressive disorder or bipolar affective disorder (current episode depression). Diagnosis of a major depressive disorder or bipolar affective disorder (DSM-5) will be confirmed by the structured diagnostic Mini International Neuropsychiatric Interview (MINI; updated Version 7 for DSM-5).

You may not qualify if:

• Current involuntary admission.
• Medical condition rendering unfit for ketamine/midazolam.
• Currently taking any of the contraindicated medications that may alter the pharmacokinetics of ketamine.
• Active suicidal intention.
• Dementia.
• Lifetime history of schizophrenia or schizoaffective disorder; active anorexia nervosa or bulimia nervosa in the past 12 months; alcohol or other substance use disorder (with the exception of nicotine) in the previous six months; any DSM-5 disorder other than a major depressive episode (unipolar or bipolar) as the primary presenting problem.
• Electroconvulsive Therapy (ECT) administered within the last two months.
• Pregnancy, breastfeeding or considering becoming pregnancy whilst on the trial for up to 12 weeks after last dose or inability to confirm use of adequate contraception during the trial.
• Breastfeeding women.

Sponsors & Collaborators

• University of Dublin, Trinity College: lead

Study Sites (1)

St Patrick's Univeristy Hospital

Dublin, D8, Ireland

Location

Related Publications (3)

• Jelovac A, McCaffrey C, Terao M, Shanahan E, Whooley E, McDonagh K, McDonogh S, Loughran O, Shackleton E, Igoe A, Thompson S, Mohamed E, Nguyen D, O'Neill C, Walsh C, McLoughlin DM. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. 2025 Dec 1;82(12):1216-1224. doi: 10.1001/jamapsychiatry.2025.3019.

  PMID: 41123905 DERIVED

• Jelovac A, McCaffrey C, Terao M, Shanahan E, Mohamed E, Whooley E, McDonagh K, McDonogh S, Igoe A, Loughran O, Shackleton E, O'Neill C, McLoughlin DM. Study protocol for Ketamine as an adjunctive therapy for major depression (2): a randomised controlled trial (KARMA-Dep [2]). BMC Psychiatry. 2023 Nov 16;23(1):850. doi: 10.1186/s12888-023-05365-9.

  PMID: 37974160 DERIVED

• McCaffrey J, Hunter A. Protocol Development for a Qualitative Methodological Study Within a Trial (Qual-SWAT): The KARMA-Dep-2 Trial. HRB Open Res. 2023 Nov 20;6:29. doi: 10.12688/hrbopenres.13721.2. eCollection 2023.

  PMID: 37361338 DERIVED

Related Links

• Research Team Website

MeSH Terms

Conditions

Depressive Disorder; Bipolar Disorder

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Bipolar and Related Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Declan M McLoughlin, PhD

  University of Dublin, Trinity College and St Patrick's Mental Health Services

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 20, 2021
• First Posted: June 25, 2021
• Study Start: September 13, 2021
• Primary Completion: April 18, 2024
• Study Completion: August 12, 2024
• Last Updated: February 13, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

IE (1)