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Trial registered on ANZCTR


Registration number
ACTRN12625001087448
Ethics application status
Approved
Date submitted
29/07/2025
Date registered
7/10/2025
Date last updated
7/10/2025
Date data sharing statement initially provided
7/10/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploring how ketamine affects the brain function in people with difficult-to-treat depression.
Scientific title
Neural Mechanisms of Ketamine Antidepressant Treatment 2.0: Exploring how ketamine affects the brain function in people with difficult-to-treat depression.
Secondary ID [1] 314853 0
Nil known
Universal Trial Number (UTN)
Trial acronym
NeuroKet 2.0
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 338127 0
Condition category
Condition code
Mental Health 334412 334412 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with difficult-to-treat depression will receive a single subcutaneous injection of 0.75mg/kg ketamine. The intervention is administered under medical supervision in a controlled clinical setting. Neuroimaging assessments (7T fMRI) will be conducted pre- and 24-48 hours post-injection to evaluate changes in habenula activity and connectivity.
Intervention code [1] 331454 0
Treatment: Drugs
Comparator / control treatment
This study will be conducted as a 2-arm RCT where the clinical control group will include DTD participants. An additional healthy control group will also be included, these participants will not be randomised to receive any injections and will only undergo a single fMRI scan.

Participants in the control group will receive a single subcutaneous injection of 0.9% saline (placebo), matched in volume and appearance. Procedures for neuroimaging and symptom assessment will be identical to the active arm.

DTD participants in the clinical control group will receive a single subcutaneous injection of 0.9% saline (placebo). Procedures for neuroimaging and symptom assessment will be identical to the active (ketamine) arm. Participants in the healthy control group will not receive any subcutaneous injection and are not involved with the subcutaneous aspect of the research study.
Control group
Placebo

Outcomes
Primary outcome [1] 342111 0
Change in habenula activity from baseline to 24-48 hours post-intervention, measured via BOLD signal using ultra-high field (7T) functional MRI following a single subcutaneous injection of 0.75mg/kg ketamine.
Timepoint [1] 342111 0
Baseline and then one time point that must fall within 24-48 hours post-injection.
Secondary outcome [1] 449586 0
1. Change in depressive symptom from baseline to 24-48 hours post-injection, measured by the Montgomery-Asberg Depression Rating Scale (MADRS)
Timepoint [1] 449586 0
Baseline and then one time point that must fall within 24-48 hours post-injection.
Secondary outcome [2] 449587 0
2. Change in anxiety symptoms from baseline to 24-48hours post-injection, assessed using the Generalised Anxiety Disorder-7 (GAD-7) scale.
Timepoint [2] 449587 0
Baseline and then one time point that must fall within 24-48 hours post-injection.
Secondary outcome [3] 449588 0
3. Change in hedonic capacity from baseline to 24-48 hours post-injection, measured by the Snaith-Hamilton Pleasure Scale (SHAPS)
Timepoint [3] 449588 0
Baseline and then one time point that must fall within 24-48 hours post-injection.
Secondary outcome [4] 451109 0
4. Change in depressive symptoms from baseline to 24-48 hours post-injection, measured by the Quick inventory of Depressive Symptomatology - Clinician Rated (QIDS-C), with comparisons between DTD participants and healthy controls and between ketamine and placebo groups
Timepoint [4] 451109 0
Baseline and then one time point that must fall within 24-48 hours post-injection
Secondary outcome [5] 451111 0
Change in photosensitivity levels from baseline to 24-48 hours post-injection, measured by a validated photosensitivity assessment tool, with comparisons between clinical and control participants, and between ketamine and placebo groups.
Timepoint [5] 451111 0
Baseline and then one time point that must fall within 24-48 hours post-injection
Secondary outcome [6] 451112 0
Change in motivational and affective processes, assessed by the Behavioural Activation System (BAS) scale, from baseline to 24-48 hours post-injection, with comparisons between DTD participants and healthy controls, and between ketamine and placebo groups
Timepoint [6] 451112 0
Baseline and then one time-point that must fall within 24-48 hours post-injection
Secondary outcome [7] 451113 0
Change in circadian preference from baseline to 24-48 hours post-injection, measured using the Morningness-Eveningness Questionanire (MEQ), with comparisons between DTD and healthy controls and between ketamine and placebo groups.
Timepoint [7] 451113 0
Baseline and then one-time point that must fall within 24-48 hours post-injection.
Secondary outcome [8] 451114 0
Change in sleep patterns assessed using actigraphy, comparing one week prior to subcutaneous injection with one week following injection, with comparisons between DTD participants and between ketamine and placebo groups.
Timepoint [8] 451114 0
One week pre-injection and one week post injection.
Secondary outcome [9] 451115 0
Change in sleep (passive sensing proxy), assessed via AWARE-light passive mobile sensing, comparing one week prior to subcutaneous injection with one week following injection; between-group comparisons include DTD vs healthy controls and, within DTD, ketamine vs placebo.
Timepoint [9] 451115 0
One week pre-injection and one week-post injection (clinical participants); controls one week pre-/post-scan.
Secondary outcome [10] 451898 0
Change in behavioural activation, assessed via AWARE-light passive mobile sensing, comparing one week prior to subcutaneous injection with one week following injection; DTD vs healthy controls and ketamine vs placebo (clinical)
Timepoint [10] 451898 0
One week pre-injection and one week post-injection (clinicals); one week pre-/post-scan (controls)
Secondary outcome [11] 451900 0
Change in circadian rhythms (passive sensing proxy), assessed via AWARE-light passive mobile sensing, comparing one week prior to subcutaneous injection with one week following injection; DTD vs healthy controls and ketamine vs placebo (clinical)
Timepoint [11] 451900 0
One week pre-injection and one week-post-injection (clinicals); one week pre-/post-scan (controls)
Secondary outcome [12] 451902 0
Change in social engagement, assessed via AWARE-light passive mobile sensing, comparing one week prior to subcutaneous injection with one week following injection; DTD vs healthy controls and ketamine vs placebo (clinical)
Timepoint [12] 451902 0
One week pre-injection and one week post-injection (clinicals), one week pre-/post-scan (clinicals)
Secondary outcome [13] 451903 0
Change in environmental engagement, assessed via AWARE-light passive mobile sensing, comparing one week prior to subcutaneous injection with one week following injection; DTD vs healthy controls and ketamine vs placebo (clinical)
Timepoint [13] 451903 0
One week pre-injection and one week post-injection (clinical); one week pre-/post-scan (controls)

Eligibility
Key inclusion criteria
Clinical Participants
• Age 18 – 65 at the time of informed consent;
• Meets DSM-5 criteria for major depressive disorder (MDD), with a current major depressive episode (MDE), confirmed via the MINI
• Insufficient response to at least 2 adequate trials of antidepressant medications, as determined by study doctor;
• Ability to provide written informed consent (including adequate intellectual capacity and fluency in the English language), as determined by the, study doctor or delegate.
Control Participants
• Age 18-65;
• Ability to provide written informed consent (including both adequate intellectual capacity and fluency in the English language) as determined by a study doctor or delegate; and
• No diagnosis of major depressive disorder
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Clinical Participants
• Severe disturbance such that the patient would be unable to comply with study requirements
• History or current diagnosis of a psychotic or bipolar disorder as assessed using the MINI
• Any unstable medical condition, or medical or pharmaceutical contraindication to ketamine
• Any history of a ketamine use disorder of any severity or moderate-to-severe substance use disorder (for other drugs) within the past 6 months
• Contraindications to MRI

Control Participants (healthy controls)
• Severe disturbances that the participant would be unable to comply with the requirements of informed consent or comply with the study protocol, as determined by a study doctor or delegate;
• Any current or past mental health disorder diagnoses as assessed through the MINI;
• Any unstable medical condition as determined by the study doctor that may be contraindicative to MRI (e.g., epilepsy);
• Currently prescribed psychoactive medication;
• Contraindications to MRI

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be implemented using REDCap's randomisation module. Allocation will be concealed from participants, researchers, and outcome assessors until after data lock.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation sequences will be generated using computer-generated random allocation sequence via REDCap, stratified by group (depression vs healthy contorl)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
This study will be conducted as a 2-arm RCT where DTD participants may be randomised to the treatment group or the clinical control group. An additional healthy control group will also be included, these participants will not be randomised to receive any injections and will only undergo a single MRI.

The purpose of the healthy control group is to determine whether any longitudinal changes that occur in the between treatment arms are a normalisation of funtioning or compensatory mechanisms. As such, the primary comparison using this group will be comparing the healthy controls to the clinical group at baseline, however, this effect will aid in the interpretation of the treatment effects.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Whole-brain fMRI general linear analyses and dynamic causal modelling (using SPM12) will be applied to examine longitudinal (pre- vs. post-subcutaneous injection) and between-group (ketamine vs. placebo) effects across three tasks, adopting conservative whole-brain (FWE-corrected) thresholds. Parametric Empirical Bayes (PEB) will be used to assess group differences in directed functional interactions between implicated regions

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/02/2026
Actual
Date of last participant enrolment
Anticipated
6/12/2027
Actual
Date of last data collection
Anticipated
20/12/2027
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 319411 0
Government body
Name [1] 319411 0
National Health and Medical Research Council
Country [1] 319411 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Country
Australia
Secondary sponsor category [1] 321896 0
None
Name [1] 321896 0
Address [1] 321896 0
Country [1] 321896 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 318565 0
The Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 318565 0
Ethics committee country [1] 318565 0
Australia
Date submitted for ethics approval [1] 318565 0
12/12/2024
Approval date [1] 318565 0
07/08/2025
Ethics approval number [1] 318565 0
HREC/113357/MH-2024

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 142770 0
Prof Christopher Davey
Address 142770 0
University of Melbourne, Alan Gilbert Building, Level 3, 161 Barry Street, Carlton, VIC, 3053
Country 142770 0
Australia
Phone 142770 0
+61 3 8344 5509
Fax 142770 0
Email 142770 0
[email protected]
Contact person for public queries
Name 142771 0
Christopher Davey
Address 142771 0
University of Melbourne, Alan Gilbert Building, Level 3, 161 Barry Street, Carlton, VIC, 3053
Country 142771 0
Australia
Phone 142771 0
+61 3 8344 5509
Fax 142771 0
Email 142771 0
[email protected]
Contact person for scientific queries
Name 142772 0
Christopher Davey
Address 142772 0
University of Melbourne, Alan Gilbert Building, Level 3, 161 Barry Street, Carlton, VIC, 3053
Country 142772 0
Australia
Phone 142772 0
+61 3 8344 5509
Fax 142772 0
Email 142772 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Any type of analysis (i.e. no restrictions on data re-use)
• Systematic reviews and meta-analyses
• Studies exploring new research questions
• Studies testing whether findings can be repeated or confirmed
• Teaching research methods or developing new statistical techniques
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.