Trial Review

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Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12625000528459
Ethics application status
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Approved
Date submitted
Help: Date submitted
17/04/2025
Date registered
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26/05/2025
Date last updated
Help: Date last updated
31/08/2026
Date data sharing statement initially provided
Help: Data sharing statement date
26/05/2025
Type of registration
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Prospectively registered

Titles & IDs
Public title
Optimised Transcranial Magnetic Stimulation for the Treatment of Depression (OptiTMS)
Scientific title
Assessing the impact of Next Generation Therapeutic Brain Stimulation on Depression symptoms in adults with treatment-resistant depression
Additional trial identifiers [1] 314233 0
None
Universal Trial Number (UTN)
U1111-1321-7305
Trial acronym
OptiTMS
Related trial records

Health condition
Health condition(s) studied:
Treatment-resistant depression 337139 0
Condition category
Condition code
Mental Health 333562 333562 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of the intervention or exposure
Transcranial Magnetic Stimulation (TMS) is a promising non-invasive therapy (ie. it does not involve surgery or the introduction of instruments into the body) for treatment of difficult to treat depression, but while life-changing for some individuals, others receive little benefit. Emerging research suggests that TMS clinical benefits might be related to the precise part of the brain at which TMS is delivered.

This study aims to compare the clinical benefits of two different methods of TMS treatment delivery. We will compare current TMS treatment where the stimulation target is based on the size of a person’s scalp to a newer approach where the stimulation target is more tailored and specific (optimised) and based on a person’s brain Magnetic Resonance Imaging (MRI) scan image. Both treatment methods target areas in the front of the brain and use a standard daily 4-week course of TMS normally used in clinical care. We are internationally recognised for our expertise in this area.

TMS is an established and approved therapy for treatment of difficult to treat depression under the Medicare Benefits Scheme. The TMS device used in this study has been approved by the Therapeutic Goods Administration for the treatment of depression.

TMS therapy will be delivered once daily, 5x per week (M-F) for 4 weeks by a trained clinician, following completion of an MRI scan up to a week before the first treatment session.

TMS will be administered with a magnetic stimulator using a figure-of-8 coil. Resting motor threshold will be defined as 5/10 muscle twitches at the first dorsal interosseus muscle elicited by single pulse TMS delivered to the motor cortex representation of this muscle. One session of intermittent theta burst stimulation will be delivered in each treatment session. Intermittent theta burst stimulation will be delivered at 100% of resting motor threshold (no distance adjustment, 600 pulses; triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off; 600 pulses per session; total duration of 3 min 9s).

The dorsolateral prefrontal cortex (DFPLC) stimulation site will be individually tailored according to brain connectivity with the subgenual cingulate cortex (SGC); this computational pipeline is detailed in Cash et al., 2021. To ensure blinding, the Beam F3 coordinate will be measured manually for all individuals prior to commencing the course of treatment and all TMS sessions will be performed using neuronavigation. The aim of the present work is to compare two of these methods, whereby the neuronavigated DLPFC target is informed by person-specific brain connectivity but remains within the bounds of the conventional stimulation area.
Intervention code [1] 330847 0
Treatment: Devices
Description of the comparator or control
Half of the trial participants will receive standard TMS treatment daily for 4 weeks, where the stimulation target is based on the size of a person’s scalp. This acts as the active control group.

TMS therapy will be delivered once daily, 5x per week (M-F) for 4 weeks by a trained clinician, following completion of an MRI scan up to a week before the first treatment session.

TMS will be administered with a magnetic stimulator using a figure-of-8 coil. Resting motor threshold will be defined as 5/10 muscle twitches at the first dorsal interosseus muscle elicited by single pulse TMS delivered to the motor cortex representation of this muscle. One session of intermittent theta burst stimulation will be delivered in each treatment session. Intermittent theta burst stimulation will be delivered at 100% of resting motor threshold (no distance adjustment, 600 pulses; triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off; 600 pulses per session; total duration of 3 min 9s).

The ‘treatment-as-usual’ ‘Beam-F3’ coordinate, which approximates the F3 electrode position, will be used as the target. To ensure blinding, the Beam F3 coordinate will be measured manually for all individuals prior to commencing the course of treatment. The corresponding MRI coordinate will be recorded using neuronavigation. When staff are provided coordinates for TMS treatment, they will be blinded as to whether these correspond to optimised or Beam- F3 coordinates. All TMS sessions will be performed using neuronavigation to ensure blinding.
Control group
Active

Outcomes
Primary outcome [1] 341141 0
MADRS score
Timepoint [1] 341141 0
Treatment end (week 4).
Secondary outcome [1] 446484 0
Sustained remission and response following TMS treatment (composite secondary outcome)
Timepoint [1] 446484 0
1, 3 and 6 months post final TMS treatment session.
Secondary outcome [2] 446486 0
Change in depressive symptoms (self-rated)
Timepoint [2] 446486 0
Baseline, the end of treatment each week, and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [3] 446487 0
Change in the burden of disease on daily life
Timepoint [3] 446487 0
Baseline, the end of treatment and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [4] 446488 0
Resource use and costs; Cost-effectiveness of neuronavigated vs scalp-based TMS
Timepoint [4] 446488 0
Baseline, treatment end, and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [5] 446489 0
Change in depressive rumination
Timepoint [5] 446489 0
Baseline, start of treatment week 3, end of treatment week 4, and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [6] 447453 0
Quality-adjusted life years (QALYs) for use in the economic evaluation
Timepoint [6] 447453 0
Baseline, treatment end, and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [7] 453169 0
Assess which anxiety symptoms are responsive to TMS stimulation target
Timepoint [7] 453169 0
Treatment start and end, and at 1, 3 and 6 months post final TMS treatment session.
Secondary outcome [8] 453170 0
Immunometabolic profile for MDD
Timepoint [8] 453170 0
Baseline, treatment end and at 1 month post final TMS treatment session.
Secondary outcome [9] 467146 0
Treatment response (defined as 50% or higher reduction in MADRS score from baseline). This outcome was previously the primary outcome, Therefore, now it has been added as a secondary outcome, The change in outcome was implemented relative to participant recruitment i.e. before recruitment commenced.
Timepoint [9] 467146 0
At treatment end (week 4).
Secondary outcome [10] 467147 0
Depression remission (defined as MADRS < 10). This outcome was previously the part of the primary outcome, Therefore, now it has been added as a secondary outcome, The change in outcome was implemented relative to participant recruitment i.e. before recruitment commenced.
Timepoint [10] 467147 0
At treatment end (week 4).

Eligibility
Key inclusion criteria
• MADRS score greater than or equal to 20 (moderate-to-severe depression severity) within 7 days of baseline visit
• Diagnosis of major depressive episode (MDE), in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context of unipolar major depressive disorder or bipolar affective disorder.
• Failure to respond to adequate trials of 2 antidepressant medications which involved treatment for minimum 4 weeks at effective dose.
• No change to antidepressant medication and other psychoactive medications in the four weeks prior to screening, nor during the study 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 patient’s care.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Healthy volunteers
No
Key exclusion criteria
• 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; defined as 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.
• Presence of acute medical illness that could interfere with study participation, including significant neurological disorder that will affect the participant’s response to TMS.
• 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 =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 and CPI.
• Significant suicide risk, as informed by the Columbia-Suicide Severity Rating Scale (C-SSRS), at the discretion of the study doctor and CPI.
• 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.

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)
The randomisation list will be computer-generated by an independent statistician and carried out centrally to ensure concealment and will be loaded and locked in the study’s REDCap database. TMS administrator will not have knowledge of treatment assignment after randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible individuals will be randomised to scalp-based TMS or optimised neuronavigated TMS using randomly permuted blocks of varying sizes in a 1:1 ratio, stratified by study site, sex, history of failed TMS treatments and depression severity.
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary outcomes
The primary outcome will be analysed using a constrained longitudinal data analysis (cLDA) model based on available cases [1]. This model assumes a common mean across groups at baseline and a different mean for each group at each follow-up time point. The response will consist of all MADRS total score measurements (at baseline, and at end of treatment weeks 2 and 4), and the model will include factors representing treatment group, time (categorical), and group-by-time interaction, and random effects to account for clustering by participant. The model will also be adjusted for stratification factors, study site, sex, and treatment resistance (low/high). The primary hypothesis will be evaluated by estimating the mean difference between intervention and control groups in MADRS total score at end of treatment (4 weeks), with a two-sided 95% confidence interval, and a p-value.
As cLDA assumes a common baseline mean across groups, this assumption will be assessed. If clinically meaningful baseline differences are observed, a standard linear mixed-effects model adjusting for baseline outcome will be fitted, with 2- and 4-week follow-up measurements included as outcomes. Standard diagnostic plots will be used to check for model assumptions.
Planned subgroup analyses will be performed for the primary outcome by stratification factors study site (RMH/SVH/QNC/BDI), sex (male/ female), and treatment resistance (low/high). Heterogeneity of treatment effects across subgroups will be explored by including the main subgroup effect, and subgroup-by-treatment, subgroup-by-time, and subgroup-by-treatment-by-time interactions in the primary cLDA model.
Sensitivity and supplementary analyses for the primary outcome will be conducted to assess the robustness of the findings, including alternative modelling approaches and missing data assumptions, with full details to be specified in the statistical analysis plan.

Secondary outcomes
Remission and response at end of treatment will be analysed using log-binomial regression models, adjusted for baseline MADRS score. Sustained remission and response will be analysed using mixed-effects logistic regression models. Longer-term MADRS scores (measured at 1, 3, and 6 months following treatment completion), and RRS, IDS-SR30, GAD-7, AQoL-8D, and C-SSRS outcomes will be analysed similarly to the primary outcome where baseline measurements are available or using linear mixed-effects models as appropriate. All analysis models will be adjusted for the stratification factors study site, sex, and treatment resistance (low/high). Exploratory analyses examining associations between immunometabolic markers and depression severity over time will be performed as appropriated and detailed in the statistical analysis plan.

Adverse events
Frequencies (percentage) of participants with one or more treatment emergent AEs will be summarised by treatment group. All treatment emergent AEs, all treatment emergent AEs potentially related to study treatment, all treatment emergent SAEs and all treatment emergent SAEs potentially related to study treatment will be summarised. Specific AEs of special interest will be outlined in the statistical analysis plan and summarised. The incidence of AEs, and their severity, as well as the incidence of participants who withdraw due to an AE will be tabulated. A participant listing of all treatment emergent AEs, and AEs causing study discontinuation will be presented.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/11/2025
Actual
8/05/2026
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/05/2029
Actual
Sample size
Target
310
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 318749 0
Government body
Name [1] 318749 0
NHMRC
Country [1] 318749 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Country
Australia
Secondary sponsor category [1] 321194 0
None
Name [1] 321194 0
Address [1] 321194 0
Country [1] 321194 0
Other collaborator category [1] 283483 0
Hospital
Name [1] 283483 0
St Vincent's Hospital
Address [1] 283483 0
Country [1] 283483 0
Australia
Other collaborator category [2] 283484 0
Other
Name [2] 283484 0
Black Dog Institute
Address [2] 283484 0
Country [2] 283484 0
Australia
Other collaborator category [3] 283485 0
Hospital
Name [3] 283485 0
Avive Clinic
Address [3] 283485 0
Country [3] 283485 0
Australia
Other collaborator category [4] 283486 0
Hospital
Name [4] 283486 0
Royal Melbourne Hospital
Address [4] 283486 0
Country [4] 283486 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317364 0
The Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 317364 0
Ethics committee country [1] 317364 0
Australia
Date submitted for ethics approval [1] 317364 0
19/03/2024
Approval date [1] 317364 0
10/04/2025
Ethics approval number [1] 317364 0

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

Contacts
Principal investigator
Name 140814 0
A/Prof Robin Cash
Address 140814 0
Level 3, 161 Barry St. Carlton The University of Melbourne, Victoria 3010
Country 140814 0
Australia
Phone 140814 0
+61 3 8344 4000
Fax 140814 0
Email 140814 0
[email protected]
Contact person for public queries
Name 140815 0
Ms Alisa Turbic
Address 140815 0
Level 3, 161 Barry St. Carlton The University of Melbourne, Victoria 3010
Country 140815 0
Australia
Phone 140815 0
+61 3 8344 4000
Fax 140815 0
Email 140815 0
[email protected]
Contact person for scientific queries
Name 140816 0
Robin Cash
Address 140816 0
Level 3, 161 Barry St. Carlton The University of Melbourne, Victoria 3010
Country 140816 0
Australia
Phone 140816 0
+61 3 8344 4000
Fax 140816 0
Email 140816 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: The PI has not yet decided whether IPD will be made available on public directories.



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.