ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12612000321842

Ethics application status

Approved

Date submitted

10/02/2012

Date registered

21/03/2012

Date last updated

22/04/2022

Date data sharing statement initially provided

22/04/2022

Type of registration

Retrospectively registered

Titles & IDs

Public title

Investigating the effect of treatment dose on clinical response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.

Scientific title

A Study of the Effect of Dose on Response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.

Secondary ID [1]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Treatment Resistant Major Depression

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Repetitive Transcranial Magnetic Stimulation (rTMS).

TMS will be administered with a Medtronic Magpro30 magnetic stimulator using a 70mm figure-of-eight coil. Prior to the commencement of treatment TMS, single pulse TMS will be used to measure the resting motor threshold (RMT) for the abductor pollicis brevis (APB) in the right hand using standard methods.

Patients will be randomised into one of four treatment conditions:

1. High dose Low Frequency rTMS applied to the right prefrontal cortex: Application of 2 continuous trains of 1 Hz rTMS of 30 minutes duration at 120% of the resting motor threshold (3600 pulses per session over 60 minutes).

2. High dose High Frequency rTMS applied to the left prefrontal cortex: Application of 125 trains of 10 Hz rTMS. 4.5 second trains will be applied at 120% of the resting motor threshold with a 15.5 second inter-train interval (5625 pulses per session over 41.6 minutes).

3. Standard dose Low Frequency rTMS applied to the right prefrontal cortex: Application of 1 continuous train of 1 Hz rTMS of 20 minutes duration at 120% of the resting motor threshold (1200 pulses per session over 20 minutes).

4. Standard dose High Frequency rTMS applied to the left prefrontal cortex: This will involve the application of 50 trains of 10 Hz rTMS. 4.5 second trains will be applied at 120% of the resting motor threshold with a 20.5 second inter-train interval (2250 pulses per session over 20.8 minutes).

Each treatment will be administered for up to four weeks, five days per week (total of 20 treatment sessions). Patients will receive an assessment at baseline, 1, 2, 3 and 4 weeks (briefer assessments at weeks 1 and 3), and the primary study analysis will be based on this data. Patients may terminate treatment if they have responded at 2, 3 or 4 weeks.

Patients who do not respond to one of the low dose treatment arms will be offered crossover treatment to the high dose condition using the opposite form of stimulation. Patients who do not respond to one of the high dose conditions will be offered the high dose form of stimulation applied to the opposite hemisphere.

A subset of participants will also take part in a sub-study looking at potential predictors of response to rTMS treatment, involving participation in some computer-based tasks and MRI imaging.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

Standard dose low frequency and high frequency repetitive Transcranial Magnetic Stimulation, as described above.

We will also recruit a group of up to 50 healthy controls, age and gender matched to the patient group, to participate in the brain imaging arm of the study. This will allow analyses of the behavioural assessment of reward and MRI data in relation to treatment response to be compared between patients and control participants. In turn, it will allow additional questions to be addressed in regards to the degree to which decision-making on these tasks varies from normal levels of function, and allow us to analyse the degree to which the relevant imaging variables differ from normal.

Control group

Dose comparison

Outcomes

Primary outcome [1]

Primary Outcome 1: change in severity of depressive symptoms, defined as:

Hamilton Depression Rating Scale (HAMD; 17 item version) - Clinical response defined as a reduction of at least 50% from baseline, clinical remission defined as a score <= 7

Timepoint [1]

Baseline, and after every 5 treatments (weeks 1, 2, 3, 4)

Secondary outcome [1]

Predictors of antidepressant response to TMS.

Specifically, we will explore the potential predictors of antidepressant response to rTMS using brain imaging analyses, and the use of tasks related to risk and reward decision making, in a subset of participants:

1. We will conduct an assessment of decision making related to reward with several computer based experimental tasks (eg. the Ultimatum Game, Signal Detection Task).

2. We will use the MRI data to model the differences between patients and controls in subcortical activation patterns induced by the decision making task, and model the relationship between activation and response to treatment using response and other relevant clinical variables in regression analyses.

Timepoint [1]

Analysis of a series of scans obtained in the one scanning session. Analysis will occur at the end of the study once all data has been collected.

Eligibility

Key inclusion criteria

Patients with depression:
1. Have a DSM-IV diagnosis of a major depressive episode

2. Have failed to respond to adequate antidepressant medical therapy. This will be defined by at least two courses of antidepressant medication (from two medication classes) at therapeutic doses for a minimum of six weeks. Adequate daily dose will be considered to be a minimum of: 150mg of Imipramine or equivalent for tricyclic antidepressants, 20mg of Fluoxetine or equivalent for serotonin re-uptake inhibitors, 600mg of Moclobemide, 600mg of Nefazadone, 150mg of Venlafaxine, 60mg of Phenelzine or equivalent for monoamine oxidase inhibitors

3. Have a Hamilton Depression Rating Scale of > 16 (moderate – severe depression)

4. Have had no increase in, or initiation of new antidepressant therapy in the 4 weeks prior to screening.

Healthy controls for the scanning sub study:
1. No personal history of psychiatric illness as determined via clinical interview.

Minimum age

18 Years

Maximum age

80 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Have an unstable medical condition, neurological disorder or any history of a seizure disorder, or are currently pregnant or lactating

For depression participants only:
2. In the opinion of the investigator, are at sufficient risk of suicide to require immediate ECT

3. Have a current DSM-IV diagnosis of substance abuse or dependence disorder, a diagnosis of a personality disorder or another Axis 1 disorder.

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)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

17/08/2011

Actual

1/02/2012

Date of last participant enrolment

Anticipated

Actual

30/09/2015

Date of last data collection

Anticipated

Actual

30/10/2015

Sample size

Target

300

Accrual to date

Final

300

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Victoria Clinic - Prahran

Recruitment postcode(s) [1]

3181 - Prahran

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

Australia

Primary sponsor type

Individual

Name

Professor Paul Fitzgerald

Address

Monash Alfred Psychiatry Research Centre
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Clinic Human Research Ethics Committeee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

10/08/2011

Ethics approval number [1]

194

Summary

Brief summary

Major depressive disorder is a severe illness of high prevalence. A significant percentage of patients fail to respond to standard treatments and continue to experience marked disability and high morbidity. Repetitive transcranial magnetic stimulation (rTMS), which is a non-invasive means of stimulating nerve cells in superficial areas of the brain, is a promising therapy for those with treatment-resistant depression. Previous research conducted by our group clearly indicates that rTMS has antidepressant activity and that the response to rTMS is clinically meaningful in some patients. Whilst several forms of rTMS are clearly effective, no one type of rTMS has demonstrated markedly greater responses that other approaches.  In recent years interest has developed into whether the dose of rTMS, in particular the number of pulses applied, is related to response to treatment (the percentage of patients that respond to treatment, the ‘response rate’).  However, as there is a considerable time cost to higher dose protocols, their usefulness requires systematic evaluation.  

Therefore, the primary goal of this study is to examine whether response to rTMS is greater or more rapid when treatment is applied at a higher dose.  To do this we will compare standard and high dose strategies for both low frequency rTMS applied to the right prefrontal cortex, and high frequency rTMS applied to the left prefrontal cortex.  A secondary goal of the study is to explore potential predictors of antidepressant response to rTMS using brain imaging analysis.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Paul Fitzgerald

Address

ECIMH
888 Toorak rd, Victoria, 3184

Country

Australia

Phone

+61 3 9805 4287

Fax

paul.fitzgerald@monash.edu

Contact person for public queries

Name

Professor Paul Fitzgerald

Address

MAPrc
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181

Country

Australia

Phone

+61 3 9076 6564

Fax

p.fitzgerald@alfred.org.au

Contact person for scientific queries

Name

Professor Paul Fitzgerald

Address

MAPrc
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181

Country

Australia

Phone

+61 3 9076 6564

Fax

p.fitzgerald@alfred.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

ethics not obtained for this data use

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

Source	Title	Year of Publication	DOI
Embase	A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression.	2020	https://dx.doi.org/10.1016/j.brs.2019.09.001

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically