Trial Review

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Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12626001294347p
Ethics application status
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Not yet submitted
Date submitted
Help: Date submitted
2/10/2026
Date registered
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28/10/2026
Date last updated
Help: Date last updated
28/10/2026
Date data sharing statement initially provided
Help: Data sharing statement date
28/10/2026
Type of registration
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Prospectively registered

Titles & IDs
Public title
D-Cycloserine Augmentation of Optimised Accelerated TMS for Treatment Resistant Depression (END-Depression study)
Scientific title
D-Cycloserine Augmentation of Optimised Accelerated TMS for Treatment-Resistant Depression (END-Depression study)
Additional trial identifiers [1] 318065 0
Protocol Number: 37019
Universal Trial Number (UTN)
Trial acronym
END-Depression
Related trial records

Health condition
Health condition(s) studied:
Major depressive disorder 343084 0
Treatment resistant depression 343085 0
Condition category
Condition code
Mental Health 339176 339176 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of the intervention or exposure
The intervention comprises a computational pipeline developed by the researchers to individually tailor the transcranial magnetic stimulation (TMS) target based on each participant's brain connectivity, as determined by analysis of their functional MRI scan.

Device: Intermittent Theta Burst Stimulation (iTBS)
iTBS will be administered with a magnetic stimulator using a figure-of-8 coil or equivalent FDA-approved device. Initial treatment coil localisation and individual calibration of stimulation intensity will be conducted by TMS-trained investigators/staff using standard approaches. Each therapeutic TMS session will comprise no distance adjustment, 1200 pulses, 20Hz, 4 second inter-train interval, with six 3-minutes sessions at 100% Resting Motor Threshold (RMT) and 57 minutes of rest between session 1-6 and 15-minutes rest after session 6, for 5 consecutive days.
The treatment will be conducted at participating TMS research clinic located at St Vincent's Hospital Melbourne.

In addition, the iTBS treatment will be augmented with either placebo or 100 mg of D-cycloserine.

Drug: D-cycloserine
D-cycloserine (DCS) is a partial NMDA receptor agonist that has demonstrable impact on rTMS and TBS's neuromodulatory effects.
Participants will be asked to orally ingest one capsule 2-hours prior to their scheduled iTBS treatment time for each of the 5 days.
Other Names: Seromycin

fMRI
MRI scans will be conducted at baseline and at the end of treatment.
MRI will be conducted by an experienced radiographer at participating imaging unit.
MRI scanning will take between 45-60 minutes.
Physiological data (heart and respiratory rate) will be recorded to allow for more detailed removal of artifacts from the MRI images.
the results of the MRI are used to enable computation of an individualised TMS target, based on brain connectivity.
Intervention code [1] 334942 0
Treatment: Drugs
Intervention code [2] 334943 0
Treatment: Devices
Description of the comparator or control
Placebo Comparator: Active iTBS + placebo (glucose capsule)
Active iTBS, 6 sessions/day x 5 days + placebo x 5 days
Control group
Placebo

Outcomes
Primary outcome [1] 346411 0
Montgomery-Asberg Depression Rating Scale (MADRS) score
Timepoint [1] 346411 0
week 5 (i.e. 4 weeks post last treatment session)
Secondary outcome [1] 465753 0
Depression remission
Timepoint [1] 465753 0
week 5 (i.e. 4 weeks post last treatment session)
Secondary outcome [2] 465754 0
Depression response
Timepoint [2] 465754 0
week 5 (i.e. 4 weeks post last treatment session)
Secondary outcome [3] 465755 0
Quick Inventory of Depressive Symptoms (QIDS-SR) (self-rated)
Timepoint [3] 465755 0
Week 5 (i.e. 4 weeks post last treatment session)
Secondary outcome [4] 465756 0
6-item Hamilton Depression Rating Scale self-report (HAM-D 6 - SR)
Timepoint [4] 465756 0
Daily throughout the treatment phase (Day 1-5)
Secondary outcome [5] 465757 0
Completion rate
Timepoint [5] 465757 0
Day 5 post-6th iTBS session
Secondary outcome [6] 465758 0
To measure change in resting state functional connectivity
Timepoint [6] 465758 0
Baseline and Day 5 post-6th iTBS session (end of treatment)
Secondary outcome [7] 468818 0
Changes in cognitive performance from baseline
Timepoint [7] 468818 0
Day 5 post-6th iTBS session (end of treatment)

Eligibility
Key inclusion criteria
• Age 18 - 50.
• Diagnosis of current major depressive episode in the context of unipolar MDD, in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), using the Structured Clinical Interview for DSM-5 Disorders.
• Failure to respond to adequate trials of 2 antidepressant medications which involved treatment for minimum 4 weeks at effective dose.
• Baseline MADRS score of greater than or equal to 20 (moderate-to-severe depression severity) within 7 days of baseline (Day 0) visit.
• No change to antidepressant or psychoactive medication in the four weeks prior to screening and over the course of the study to the primary endpoint.
• No initiation of new antidepressant therapy in the four weeks prior to screening and over the course of the study to the primary endpoint.
• Ability to provide written informed consent (including adequate intellectual capacity and fluency in the English language).
• Referral from a psychiatrist or general practitioner who continues to be responsible for the participant’s care.
• Pass the TMS adult safety screening (TASS) questionnaire.
• Agree to be informed about potential incidental findings that require urgent treatment.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Healthy volunteers
No
Key exclusion criteria
• Participant likely to be unable to comply with the requirements of informed consent or comply with the study protocol, as determined by a study doctor or delegate.
• Diagnosis of psychotic disorder.
• Diagnosis of rapid cycling bipolar disorder involving greater than or equal to 4 episodes, including major depressive, manic, hypomanic, or mixed, within the past 12 months.
• Presentation is mainly due to another mental disorder other than depression, in the opinion of the study doctor.
• Presence of acute medical illness that could interfere with study participation, including significant neurological disorder that will affect the participant’s response to TMS, in the opinion of the study doctor.
• A moderate-to-severe substance use disorder (for other drugs) within the past 6 months, according to DSM-5 criteria.
• Women of child-bearing potential who are pregnant, breastfeeding, trying to become pregnant or become pregnant during the course of the trial.
• Current treatment with TMS, electroconvulsive therapy (ECT) or ketamine, or initiation of new ECT or ketamine treatment during the study period.
• Acute rTMS treatment (defined as greater than or equal to 2 sessions per week) within the past 4 months, or maintenance rTMS treatment within the past 4 weeks.
• Contraindications to Magnetic Resonance Imaging (MRI) (e.g. metallic foreign bodies, pacemaker, metal pins or metal piercings) or TMS (e.g. history of seizures or epilepsy, Cochlear implants, brain pathology detected from MRI) as evaluated by the study doctor.
• Significant suicide risk, as informed by the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Exposure to any investigational drug within the 4 weeks prior to screening or currently taking part in another intervention trial.
• A TMS target cannot be computed from MRI due to patient movement or other factors, that are considered unlikely to resolve in repeat MRI, at the discretion of the investigator.
• Benzodiazepine use exceeding 10 mg diazepam equivalents per day.
• Allergy to DCS.
• Total MADRS score changes by 30% or more from screening to baseline assessment.

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 is undertaken following recruitment, consent and allocation of a trial-specific identification number. Eligible and consented individuals will be randomised to the accelerated TMS + DCS arm or accelerated TMS + placebo arm using randomly permuted blocks of varying sizes in a 1:1 ratio. The randomisation list will be computer-generated and carried out centrally to ensure concealment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation list will be computer-generated.
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
Parallel
Other design features
Phase
Phase 0
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2027
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 30313 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 46725 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 322628 0
Government body
Name [1] 322628 0
NHMRC
Country [1] 322628 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Country
Australia
Secondary sponsor category [1] 325546 0
None
Name [1] 325546 0
Address [1] 325546 0
Country [1] 325546 0
Other collaborator category [1] 284049 0
Hospital
Name [1] 284049 0
St Vincent’s Hospital Melbourne
Address [1] 284049 0
Country [1] 284049 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 321087 0
St Vincent’s Hospital Human Research Ethics Committee
Ethics committee address [1] 321087 0
Ethics committee country [1] 321087 0
Australia
Date submitted for ethics approval [1] 321087 0
17/11/2026
Approval date [1] 321087 0
Ethics approval number [1] 321087 0

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

Contacts
Principal investigator
Name 152614 0
A/Prof Robin Cash
Address 152614 0
The University of Melbourne, Grattan Street, Parkville VIC 3010
Country 152614 0
Australia
Phone 152614 0
+61 3 8344 1000
Fax 152614 0
Email 152614 0
[email protected]
Contact person for public queries
Name 152615 0
Ms Alisa Turbic
Address 152615 0
The University of Melbourne, Grattan Street, Parkville VIC 3010
Country 152615 0
Australia
Phone 152615 0
+61 3 8344 1000
Fax 152615 0
Email 152615 0
[email protected]
Contact person for scientific queries
Name 152616 0
A/Prof Robin Cash
Address 152616 0
The University of Melbourne, Grattan Street, Parkville VIC 3010
Country 152616 0
Australia
Phone 152616 0
+61 3 8344 1000
Fax 152616 0
Email 152616 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: this will not be covered by our ethics approval



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.