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Major Depressive EpisodePhase 3KARMA-Dep2NCT04939649

Ketamine As an Adjunctive Therapy for Major Depression (2)

A Phase 3 study testing Ketamine and Midazolam in people with Major Depressive Episode and Unipolar Depression, run by University of Dublin, Trinity College at 1 site in Ireland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ketamine and Midazolam
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
63 participants
Where
1 siteIreland
Study dates
13 Sep 2021to 12 Aug 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥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).

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

1 site in 1 country.

Ireland1 site

  • St Patrick's Univeristy Hospital

    Dublin, D8

Other trials in Ireland

About this study

Official title: Ketamine As an Adjunctive Therapy for Major Depression - a Randomised Controlled Trial: [KARMA-Dep (2)]

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.

Read the detailed description

Pragmatic, randomised, controlled, parallel-group, superiority trial. Trial participants will be patients admitted to St Patrick's University Hospital for treatment of a major depressive episode. The investigators aim to recruit up to 104 participants who will be eligible for this study and randomly allocate 52 patients to each group. Both participants and assessors will be blind to treatment allocation. Eligible consented participants will be randomly allocated in a 1:1 ratio to a course of up to eight infusions of either ketamine or midazolam twice weekly over up to four weeks. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. During the allocated infusions and follow-up period patients will be monitored for treatment-related adverse events relating to both mental and physical health. Participants will also be followed-up for 24 weeks after the end of the initial randomised treatment and assessment period lasting up to four weeks, in order to identify if and when relapse occurs. During the trial, both groups will continue usual inpatient care as prescribed by their treating team.

Being tested
Ketamine, Midazolam
Keywords
ketamine, glutamate
Medical subject headings
Depressive Disorder, Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • KetamineDrug

    Also called Ketalar

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

  • MidazolamDrug

    Also called Hypnovel

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

Study groups in NCT04939649
Study groupRoleWhat they receive
KetamineExperimentalParticipants 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.
Receives: Drug: Ketamine
MidazolamActive comparatorParticipants 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.
Receives: Drug: Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 28 weeks

Secondary outcomes (12)

  1. The Clinician-Administered Dissociative States Scale (CADSS)

    The CADSS will measure dissociative symptoms, as a possible subjective side effect of either ketamine or midazolam. The CADSS consists of 23 items and scores for each item range from 0 to 4. The CADSS measures dissociative symptoms in the following domains: identity, proprioception, time perception, colour and depth perception, and other modalities. The maximum score is 92, with higher scores indicating more dissociative symptoms.

    The CADSS will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).

    Measured: 4 weeks

  2. The Brief Psychiatric Rating Scale (BPRS)

    The positive symptoms subscale of the BPRS will be used to measure psychotomimetic effects of either ketamine or midazolam. This 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each item is scored between 0 and 7. The maximum score is 28, with higher scores indicating more severe psychotic symptom.

    Participants will complete the BPRS three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).

    Measured: 4 weeks

  3. Young Mania Rating Scale (YMRS; mood item)

    The YMRS is an observer-rated assessment tool for severity of mania and hypomania. The single mood item of the YMRS, rated from 0 to 4 (representing a range from normal mood to frank euphoria), will be used to assess for possible mood elevation during the infusion sessions. Higher scores reflect more elevated mood.

    Participants will have the YMRS performed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).

    Measured: 4 week

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

    The OAA/S-R is an observer-rated assessment that will be used to measure levels of sedation experienced by participants during either ketamine or midazolam infusion. The OAA/S-R ranges in score from 1 to 5, where 1 denotes deep sleep (i.e. no response to mild prodding or shaking) and 5 denotes fully alert.

    The OAA/S-R will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).

    Measured: 4 weeks

  5. 20-item Physician Withdrawal Checklist (PWC-20)

    The PWC-20 will be used to assess for potential withdrawal symptoms during and after completion of the allocated course of ketamine/midazolam infusions. The PWC-20 is a brief checklist and each item is rated from 0 (not present) to 3 (severe). PWC-20 scores range from 0 to 60, with higher scores indicating more withdrawal symptoms with greater severity.

    The PWC-20 will be completed at screening (prior to randomisation), 24 (±1) hours after the end of the fourth and final infusions, and the 6- and 12-week follow-up timepoints.

    Measured: 16 weeks

  6. The Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR)

    The QIDS-SR is a validated, self-report measure of depressive symptoms. The QIDS-SR consists of 16 items, with each item rated on a scale from 0 to 3. Total scores range from 0 to 48, with higher scores reflecting greater burden of depressive symptoms.

    The QIDS-SR 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 items 1,2,3,4,6,7,8 \& 9 on the QIDS-SR will be carried over from -40 minutes before each infusion to +60 minutes, +120 minutes \& 24 hours after each infusion in line with the methodology of previous literature.

    Measured: 28 weeks

  7. Patient-Rated Inventory of Side Effects (PRISE)

    The PRISE is a 9-item, self-report measure that will document general adverse events experienced by patients during each infusion, by identifying and evaluating the tolerability of each adverse event. The PRISE assesses adverse events in the following symptom domains; Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning, and Other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rate whether or not the symptoms are tolerable or distressing.

    The PRISE will be completed at screening (prior to randomisation), after all infusion sessions (+120 (±10) mins after the infusion begins), and at the 6, 12 and 24 weeks follow-up time points.

    Measured: 28 weeks

  8. The Montreal Cognitive Assessment (MoCA)

    The MoCA is a rapid screening instrument for mild cognitive dysfunction. It assesses the following cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. The maximum score is 30, with higher scores indicating better cognition.

    The MoCA will be completed at screening (prior to randomisation), at +120 (±10) mins after the infusion begins during the first and final infusion sessions, and at the 12 and 24 weeks follow-up time points.

    Measured: 28 weeks

  9. EuroQol-5 dimensions-5 level scale for health status (EQ-5D-5L)

    Health-related quality-of-life will be measured using the EQ-5D-5L. The EQ-5D-5L consists of the EQ-5D descriptive system, and the EQ visual analogue scale (EQ VAS).

    The EQ-5D descriptive system includes the following five dimensions that assess an individual's self-rated health status: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is rated on a 5-point Likert scale. The digits related to each response to the five dimensions are combined into a 5-digit number, which describes the patient's health state.

    The EQ VAS includes a vertical visual analogue as a quantitative measure of subjectively rated health, with endpoints labelled as 'Best imaginable health status' and 'Worst imaginable health status'.

    The EQ-5D-5L will be administered at screening (prior to randomisation) and at the 6-, 12- and 24-week follow up time periods.

    Measured: 28 weeks

  10. Client Service Receipt Inventory (CSRI)

    The CSRI will calculate healthcare costs using the following data: sociodemographic information, usual living situation, employment status and income levels and the care services and supports used by participants. Currently prescribed medicines will also be recorded.

    Healthcare costs will be estimated using the CSRI at baseline and at the 6-, 12- and 24-week follow-up timepoints.

    Measured: 28 weeks

  11. Adverse events (AE) and serious adverse events (SAE) review

    AEs and SAEs will be reviewed at every visit. All AEs and SAEs will be reported and followed up until resolved or until final visit.

    Measured: 28 weeks

  12. Concomitant Medication

    All medications taken one month prior to participant screening will be recorded. At all other visits, concomitant medication taken since last visit will be documented. Adherence to prohibited/contraindicated medication requirements will be assessed and documented at each infusion visit.

    Measured: 28 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jun 2021
  2. Study start13 Sep 2021
  3. Primary completion18 Apr 2024
  4. Study completion12 Aug 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
63 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04939649
Sponsor's protocol ID
CRFSPN004
Other IDs
2019-003109-92, 2019
Acronym
KARMA-Dep2
Status last verified
Feb 2025
First submitted
20 Jun 2021
Last updated
13 Feb 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 41123905

  • 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.

    PubMed 37974160

  • 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.

    PubMed 37361338

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ketamine and Midazolam in people with Major Depressive Episode and Unipolar Depression, run by University of Dublin, Trinity College at 1 site in Ireland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Montgomery Asberg Depression Rating Scale-10 item version (MADRS) (time frame: 28 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04939649, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2025.

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