Comparative Effectiveness Study of Two Forms of Ketamine for Treatment-resistant Depression (TREK)

May 27, 2026 updated by: The George Institute

Comparative Effectiveness Study of Two Forms of Ketamine for Treatment-Resistant Depression: a Randomised, Rater-blinded Trial

The goal of this study is to compare the effectiveness of two formulations of ketamine - Spravato® and racemic ketamine - in people with treatment-resistant depression (TRD). The main questions it aims to answer are:

  • How the two formulations compare in terms of their effectiveness in treating TRD.
  • How the two formulations compare in their acceptability to patients, safety, effects on patient quality of life and function, and cost effectiveness.

Participants will be randomised to receive either Spravato® or racemic ketamine treatment and asked to complete some questionnaires to assess the effects on mood, treatment acceptability, side effects, quality of life and function, and health economic outcomes.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The TREK study is a randomized, prospective, rater blinded (primary outcome raters), parallel group, comparative effectiveness trial of racemic ketamine and Spravato®, comparing their effectiveness, acceptability, safety, effects on quality of life (QOL), function and cost effectiveness after 4 weeks - 6 months of treatment in people with TRD.

Participants will be recruited from clinics/hospitals that are providing racemic ketamine and Spravato® treatment services for TRD. Participants will be referred, treated and followed up as per the clinic's normal clinical practice. Participants who consent to participate in this research study will undergo other processes in addition to the standard treatment procedures provided by their clinic:

  • Randomisation to receive racemic ketamine or Spravato®.
  • Completion of questionnaires to measure treatment effects on mood, acceptability, safety, quality of life and function and cost effectiveness.

Study Type

Interventional

Enrollment (Estimated)

162

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
    • Queensland
      • Southport, Queensland, Australia, 4215
        • Recruiting
        • Gold Coast University Hospital
        • Principal Investigator:
          • Shanthi Sarma
        • Contact:
    • Victoria
      • Melbourne, Victoria, Australia, 3004
      • Parkville, Victoria, Australia, 3052
        • Recruiting
        • Royal Melbourne Hospital
        • Principal Investigator:
          • Christopher Davey
        • Contact:
          • Orli Schwartz, Study Coordinator, PHD
          • Phone Number: 61-3-8344-0944
          • Email: orli@unimelb.edu.au

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adult with treatment-resistant depression (TRD: not responded adequately to at least two different antidepressants of adequate dose and duration) who has a current depressive episode (DSM 5)
  • Assessed and attested by clinic psychiatrist as appropriate to receive either racemic ketamine or Spravato® ketamine treatment for TRD
  • MADRS score of ≥20 at study baseline, assessed by certified study rater
  • Aged ≥18 years
  • Written informed consent for research study obtained

Exclusion Criteria:

  • Not able to give informed consent
  • Any physical or mental condition which, in the opinion of the investigator, could interfere with study participation including outcome assessments
  • Any treatment with ketamine or Spravato® within 4 weeks prior to written informed consent for the research study
  • Patients who require an interpreter/translator for the clinic consent process, due to the infeasibility of obtaining an interpreter for research assessments, including self-rated scales

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Esketamine group
Dosing of esketamine intranasal spray will be guided by the Spravato® Product Information. This involves a starting dosage of 28 or 56 mg, with dose adjustment up to 84 mg as required to optimise response. Dose adjustments will be based on effectiveness and tolerability to the previous dose. The recommended treatment protocol is twice per week for 4 weeks, then weekly in weeks 5-8, then option of weekly-fortnightly "maintenance" treatment for responders. After week 8, patients may continue treatment as guided by the ketamine clinic psychiatrist.
Drug: Esketamine group

The recommended dosing for Spravato is:

Weeks 1-4:

Starting Day 1 dose:

< 65 years: 56 mg

≥ 65 years: 28 mg

Subsequent doses:

28 mg (≥ 65 years), 56 mg or 84 mg twice weekly

Weeks 5-8:

28 mg (≥ 65 years), 56 mg or 84 mg once weekly

From Week 9:

28 mg (≥ 65 years), 56 mg or 84 mg every 2 weeks or once weekly

Other Names:
  • Spravato®
Active Comparator: Racemic ketamine

Treatment administration will follow standard clinical practice in the recruiting clinic, with a recommendation to follow an evidence-based and established dose-optimising approach, given by injection, twice per week for 4 weeks, then the frequency of further treatments (week 5 - month 6) will be based on the clinical judgement of the ketamine clinic psychiatrist.

Dosing will be adjusted by the ketamine clinic psychiatrist, based on clinical response, safety and tolerability. The psychiatrist will review the patient before each treatment, over the first 4 weeks, to judge the dose level required.

Typically, dosing will begin at the standard dose of 0.5 mg/kg and adjusted using an ascending dose titration schedule if the patient has not shown clinical response and if side effects are adequately tolerated.

.
Drug: Racemic ketamine

Typically, dosing will begin at the standard dose of 0.5 mg/kg and adjusted as needed using an ascending dose titration schedule:

  1. 0.5 mg/kg
  2. 0.6 mg/kg
  3. 0.75 mg/kg
  4. 0.9 mg/kg
  5. Further increments by 0.1-0.2 mg/kg, up to max 1.5 mg/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery-Asberg Depression Rating Scale (MADRS)
Time Frame: From week 0 to week 4.

Change in score on the Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS is sensitive to change, and is commonly used for treatment trials in depression.

MADRS includes questions on ten symptoms, each of which yields a score of 0 to 6. The total score ranges from 0 to 60. The higher the MADRS score the more severe the depression. Cutoff points are for levels of depression are:

0 to 6: normal /symptom absent 7 to 19: mild depression 20 to 34: moderate depression 35 to 60: severe depression.
From week 0 to week 4.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DASS-21
Time Frame: Performed weekly from baseline to week 8 inclusive and at 6 month visit.
Depression, Anxiety and Stress Scale (DASS-21) - will be used to measure psychological distress. It consists of three 7-item subscales, with items scored on a 4-point Likert scale (0-3) and summed to obtain subscale scores.
Performed weekly from baseline to week 8 inclusive and at 6 month visit.
Speed of response - Clinical Global Impression-Improvement (CGI-I)
Time Frame: Performed weekly from week 1 to week 4 inclusive, then at week 8 and at 6 month visits.
Speed of response, assessed by number of treatments required to attain CGI-I score of ≥ 3.
Performed weekly from week 1 to week 4 inclusive, then at week 8 and at 6 month visits.
Psychotomimetic symptoms
Time Frame: Through study completion at each treatment visit, up to 6 months
Assessed via the Ketamine Side Effect Tool (KSET), designed to monitor the acute, cumulative and longer-term safety of ketamine treatment.
Through study completion at each treatment visit, up to 6 months
Suicide attempts or gestures
Time Frame: During 6-month study period
Data collected as an Adverse Event of Special Interest
During 6-month study period
Number of Participants with urinary symptoms, as assessed using the Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS)
Time Frame: Performed at baseline, week 4, week 8 and at 6 month visit.
Bladder Pain-Interstitial Cystitis Symptom Score (BPIC-SS) - a self-report symptom-based instrument that identifies moderate to severe bladder pain syndrome. Side effects of racemic ketamine/Spravato® include inflammation of the bladder endothelium. From 8 questions about bladder/urination pain, patients can score a minimum of 0 (asymptomatic) and a maximum of 38 (severe symptoms).
Performed at baseline, week 4, week 8 and at 6 month visit.
Cognitive Failure Questionnaire scores (CFQ)
Time Frame: Performed at baseline, week 4, week 8 and at 6 month visit.
Cognitive Failures Questionnaire (CFQ) is a self-rated tool to assess subjective impression of cognitive functioning. From 25 questions, patients can score a minimum of 0 (best) and a maximum of 100 (worst).
Performed at baseline, week 4, week 8 and at 6 month visit.
Ketamine liking/craving score
Time Frame: Performed at baseline, week 4, week 8 and at 6 month visit.
Ketamine liking/craving score will be used as a measure of ketamine craving/abuse. A visual analogue scale is used, where patients can score a minimum of 0 (strong dislike/no craving) and a maximum of 30 (very strong liking/constant craving).
Performed at baseline, week 4, week 8 and at 6 month visit.
Number of Participants with urinary symptoms, as assessed using the Ketamine Side Effect Tool (KSET)
Time Frame: Through study completion at each treatment visit, up to 6 months
Assessed via the Ketamine Side Effect Tool (KSET), designed to monitor the acute, cumulative and longer-term safety of ketamine treatment.
Through study completion at each treatment visit, up to 6 months
Acceptability Questionnaire
Time Frame: Performed at week 4, week 8 and at 6 month visit.

An 8-item self-rated instrument to assess the acceptability of healthcare interventions. This evaluates the constructs of affective attitude, effort burden, ethicality, perceived effectiveness, intervention coherence, self-efficacy, opportunity costs and general acceptability. Patients can score a minimum of 8 (very unacceptable) and a maximum of 40(very acceptable).

"If reporting a score on a scale, please include the minimum and maximum values, and whether higher scores mean a better or worse outcome." Appears that not all high scores are positive so makes it hard to address this issue.
Performed at week 4, week 8 and at 6 month visit.
Recovering Quality of Life Questionnaire (REQOL-10)
Time Frame: Over 6 month study period
Recovering Quality of Life, 10-item (REQOL-10) is used to assess the quality of life for people with different mental health conditions. Patients can score a minimum of 0 (poorest quality of life) and a maximum of 40 (highest quality of life).
Over 6 month study period
WHO Disability Assessment Scale (WHODAS-12)
Time Frame: Over 6 month study period
12-item WHO Disability Assessment Scale (WHODAS-12) is a 12-item self-rated assessment of health and disability. It will be used to assess functionality. Patients can score a minimum of 0 (no disability) and a maximum of 48 (complete disability).
Over 6 month study period
Patient Health Questionnaire-9 (PHQ-9)
Time Frame: Over 6 month study period
Patient Health Questionnaire-9 (PHQ-9) is a self-report screening tool designed to assess the severity of depressive symptoms in individuals and monitors symptom changes and treatment effects over time. Patients can score a minimum of 0 (no depression) and a maximum of 27 (severe depression).
Over 6 month study period
Assessment of Quality of Life Questionnaire (AQoL-8D)
Time Frame: Over 6 month study period
Assessment of Quality of Life Questionnaire (AQoL-8D) consists of 35 items covering 8 dimensions: Independent Living, Pain, Senses, Mental Health, Happiness, Coping, Relationships, and Self-worth. It will be used to assess quality of life outcomes and to facilitate the health economics analysis. There is a max patient score of 1 (perfect health) and a minimum score of 0 (deceased) based on weighted utility scores
Over 6 month study period
Resource Use Questionnaire (RUQ)
Time Frame: Over 6 month study period

The resource use questionnaire (RUQ) collects information regarding the type and number of contacts with the health system including hospitalisations, consultations and medications. The information is then 'scored' by multiplying indicative unit costs by the number of contacts for each service used. The costs per service are summed to calculate a total health sector cost.

The resource use questionnaire also collects information regarding time missed (absenteeism) and time working at reduced capacity (presenteeism) for paid work and time missed from unpaid work. The number of hours missed and working at reduced capacity from paid work will be valued using an average wage rate. The hours missed from unpaid work will be valued using a shadow cost for the value of leisure time. These costs are summed and combined with health sector costs to calculate societal costs.
Over 6 month study period
End of Treatment questionnaire
Time Frame: Used at end of the treatment period(s) over the course of the study.
Collected via case report form. Captures reason for ceasing, switching or re-starting study medication.
Used at end of the treatment period(s) over the course of the study.
Treatment Preference
Time Frame: Assessed once, prior to randomization
The Treatment Preferences questionnaire is a simple 3 item self-report questionnaire which asks participants to indicate their treatment preference for one of the 2 interventions, if any; their strength of preference (slight, moderate or strong); their reason for preference (Prefer this method of receiving the medication; Had this treatment before and benefitted; Past negative experience with the other treatment; Impression from reports, other people or media; Other (please specify))
Assessed once, prior to randomization
Stanford Expectations of Treatment Scale (SETS)
Time Frame: Assessed once, after randomization and before first treatment
The SETS is a self-report questionnaire that assesses positive and negative treatment expectations with 6 items rated on a 7-point Likert scale from 0 'not agree at all' to 6 'fully agree'; additional questions ask the responder to confirm the treatment they will receive and whether they have received it before as well as whether any specific benefits or harms/negative side effects are expected
Assessed once, after randomization and before first treatment
Montgomery-Asberg Depression Rating Scale (MADRS) score
Time Frame: At week 8, month 4 and month 6
Score on the Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS is sensitive to change, and is commonly used for treatment trials in depression. See outcome 1 for minimum and maximum values, and whether higher scores indicate a better or worse outcome.
At week 8, month 4 and month 6
Response - Montgomery-Asberg Depression Rating Scale (MADRS)
Time Frame: Weeks 4, 8 and months 4 and 6
Response (≥50% improvement in MADRS)
Weeks 4, 8 and months 4 and 6
Remission - Montgomery-Asberg Depression Rating Scale (MADRS)
Time Frame: Weeks 4, 8 and months 4 and 6
Remission (MADRS score ≤10)
Weeks 4, 8 and months 4 and 6
Difficulties in Emotion Regulation Scale-16 (DERS-16)
Time Frame: Performed at baseline and week 4
The DERS-16 is a self-report measure with established internal consistency, reliability and validity that assesses an individual's typical levels of difficulties in emotion regulation. The DERS-16 assesses five aspects of difficulties in emotion regulation: nonacceptance of emotional responses, difficulty engaging in goal-directed behaviour, impulse control difficulties, limited access to emotion regulation strategies, and lack of emotional clarity.
Performed at baseline and week 4
Level of Personality Functioning Scale-Brief Form (LPFS-BF)
Time Frame: Performed at baseline and week 4
The LPFS-BF is a 12-item self-report questionnaire that provides a first impression of impairments in personality functioning. The LPFS-BF consists of 12 items, clustered into two higher order domains: self-functioning and interpersonal functioning. Validity and sensitivity have been established in a range of samples and languages
Performed at baseline and week 4
Clinical Global Impression-Improvement (CGI-I)
Time Frame: Performed weekly from week 1 to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
The Clinical Global Impression - Improvement scale (CGI-I) is used to assess depressive symptom improvement from study baseline. The minimum value is -6 (maximum deterioration) and the maximum value is 6 (ideal improvement).
Performed weekly from week 1 to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
Clinical Global Impression-Severity (CGI-S)
Time Frame: Performed weekly from baseline to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
The Clinical Global Impression - Severity scale (CGI-S) is used to assess depressive symptom severity. The minimum value is 1 (normal) and the maximum value is 7 (among the most extremely ill patients).
Performed weekly from baseline to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: Performed weekly from baseline to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
Columbia Suicide Severity Rating Scale (C-SSRS) - short questionnaire that will be used by the clinic teams as a clinical tool to assess suicidality.
Performed weekly from baseline to week 4 inclusive, then at week 8 and at 3, 4, 5 & 6 month visits.
Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR)
Time Frame: Performed at baseline and the end of randomised treatment.
The Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) is a measure of depressive symptom severity. It consists of 16 factors across 9 different criterion domains, with items scored on a 4-point Likert scale (0-3) and summed to obtain subdomain scores.
Performed at baseline and the end of randomised treatment.
Patient Global Impression - Improvement (PGI-I)
Time Frame: Performed weekly from week 1 to week 4 inclusive, then at week 8 and at month 3, 4, 5 & 6 visits.
The Patient Global Impression - Improvement (PGI-I) measures a patient's perception of their improvement since a treatment. It consists of one question that uses a 7-point scale that asks a patient to rate their change ranging from 'very much improved' to 'very much worse'.
Performed weekly from week 1 to week 4 inclusive, then at week 8 and at month 3, 4, 5 & 6 visits.
Generalized Anxiety Disorder (GAD-7)
Time Frame: Performed at baseline, week 4 and 8, and at month 3, 4, 5 and 6 visits.
The Generalized Anxiety Disorder (GAD-7) is used to assess symptom severity of generalised anxiety disorder. It consists of 7 items that use a 4-point Likert scale (0-3) which are summed to create a total score ranging from 0 (minimal anxiety) to 21 (severe anxiety.
Performed at baseline, week 4 and 8, and at month 3, 4, 5 and 6 visits.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The George Institute

Collaborators

The University of New South Wales

Investigators

  • Principal Investigator: Colleen Loo, The University of New South Wales

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 3, 2024

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

April 1, 2027

Study Registration Dates

First Submitted

January 20, 2024

First Submitted That Met QC Criteria

February 19, 2024

First Posted (Actual)

February 26, 2024

Study Record Updates

Last Update Posted (Actual)

May 29, 2026

Last Update Submitted That Met QC Criteria

May 27, 2026

Last Verified

May 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • X23-0311

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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