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Trial registered on ANZCTR

Registration number

ACTRN12610001071011

Ethics application status

Approved

Date submitted

22/11/2010

Date registered

6/12/2010

Date last updated

29/06/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Investigating predictors of response to Transcranial Magnetic Stimulation for the treatment of depression

Scientific title

Investigating predictors of the antidepressant efficacy of Transcranial Magnetic Stimulation

Secondary ID [1]

Project 303/10

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Treatment resistant depression

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Transcranial Magentic Stimulation (TMS).

Magnetic stimulation is a non invasive technique for stimulating neural tissue. A rapid change in magnetic field induces a current in the neural tissue. If the current is of sufficient amplitude and duration it will excite nerve tissues.

Patients will receive left sided high frequncy TMS intially, if they do not respond after three weeks they will be randomised to either; continue left sided high frequnecy treatment, crossover over to right sided low frequency TMS or sequential bilateral TMS (i.e. right sided low frequency followed by left sided high frequency).

Daily treatment (Mon-Fri) at 110% of motor threshold, for between 5 and 8 weeks.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

There will be a group of healthy controls who will undergo the predictor measures at baseline for comparison.

Control group

Active

Outcomes

Primary outcome [1]

Antidepressant effects.

Montgomery Asberg Depression Rating Scale (MADRS)

A reduction of at least 50% on this rating scale indicates response.

Timepoint [1]

The MADRS will be administered at baseline, weeks 1, 4, 7 and 10.

Secondary outcome [1]

Predictors of Response to TMS.

Specifically, we will test the potential predictive capacity of several electrophysiological techniques:

1. Resting and task related frontal alpha electroencephalography (EEG) activity: Extensive research has demonstrated a relationship between resting frontal alpha activity in depression. More recent research has indicated a substantive functional role of alpha in tasks such as cognitive inhibition. This active alpha activity may provide a more functionally useful measure of alpha as it could potentially relate to response to treatment.

2. TMS-EEG measures of cortical inhibition: We have recently pioneered a technique combining single and paired pulse TMS stimulation with EEG to measure the activity of inhibitory GABAergic activity in cortical regions such as the dorsolateral prefrontal cortex (DLPFC). GABA activity has previously been shown to be reduced in patients with depression and to increase with successful treatment although no methods have been available to evaluate functional GABA activity and its relationship to treatment response before now.
3. Near infrared spectroscopy (NIRS) is a technique for non invasively measuring cortical blood flow by assaying changes in absorption and diffraction of near infrared light produced by changes in oxygenated and deoxygenated haemoglobin. We have successfully recorded blood flow changes with NIRS during prefrontal TMS and will explore whether the immediate reduction in oxygenated haemoglobin seen in local cortical regions during TMS treatment is associated with treatment response.

Timepoint [1]

The predictors will be measured at baseline weeks, 1, 4 and 7 weeks.

Eligibility

Key inclusion criteria

Have a DSM-IV diagnosis of a Major Depressive Episode (SCID II).

Are aged 18-75.

Have treatment resistant depression at Stage III of the Thase and Rush classification (27).

Have a Hamilton Depression Rating Scale (HAMD) score of > 20 (moderate to severe depression).

Have had no increase or initiation of new antidepressant (or other psychoactive) therapy in the 4 weeks prior to screening

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

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

In the opinion of the investigator, are at sufficient risk of suicide to require immediate electroconvulsive therapy.

Have a current DSM-IV diagnosis of Substance Abuse or Dependence disorder, a diagnosis of a personality disorder (SCID II) or another Axis 1 disorder.

Control participants will have no history of neurological or psychiatric illness and be taking no medications.

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)

Patients will receive left sided high frequncy TMS intially, if they do not respond after three weeks they will be randomised to either; continue left sided high frequnecy treatment, crossover over to right sided low frequency TMS or sequential bilateral TMS (i.e. right sided low frequency followed by left sided high frequency). Allocation was concealed via central randomisation by phone/fax/computer

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

Randomization will occur via the generation of a single computer number sequence.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/02/2011

Actual

21/01/2011

Date of last participant enrolment

Anticipated

Actual

2/02/2015

Date of last data collection

Anticipated

Actual

27/05/2015

Sample size

Target

120

Accrual to date

Final

113

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

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]

Hospital

Name [1]

Alfred Hospital

Address [1]

55 Commercial Road
PO Box 315 Prahran
Victoria 3181 Australia

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Human Research Ethics Committee

Ethics committee address [1]

Research & Ethics Unit
Linay Pavilion
The Alfred
55 Commercial Road
PO Box 315 Prahran
Victoria 3181 Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

22/10/2010

Ethics approval number [1]

1/10/0303

Summary

Brief summary

Major depressive disorder (MDD) is common, associated with considerable disability and high morbidity and often resistant to treatment with standard approaches (~30% of patients meet standard definitions for treatment resistant depression (TRD)). There is currently an overwhelming need in the community for the development of better and novel treatments for depression.  Despite the demand, there are relatively few treatment options available to patients with TRD. One of the only substantially new treatments developed in recent years has been repetitive transcranial magnetic stimulation (rTMS).  Despite the considerable bulk of evidence demonstrating that rTMS can be effective in the treatment of depression, a major issue that limits its wider use is that only between 40-50% of patients respond to rTMS treatment.  While this is a good response rate in a group of patients with significant depression who have failed to respond to other treatments, participation in rTMS treatment involves a considerable commitment of time and resources (stimulation is usually provided five days per week to outpatients who attend for up to six weeks). It is therefore essential to be able to identify patients who are more or less likely to respond to treatment. This research aims to provide a practical and clinically useful approach to predicting antidepressant response to rTMS treatment.  In addition, by providing greater information about the underlying causes of depression and how these interact with treatments, this research may ultimately assist in developing more effective therapies for TRD.  This would have a significant impact on the considerable numbers of Australians with depression who have tried standard therapies and yet remain significantly unwell. Therefore the current project aims to use both novel and more established neuroscience methodologies (namely electroencephalogy (EEG), TMS and near infra-red spectroscopy (NIRS)) to investigate whether such techniques can be used to predict response to rTMS treatment in depression.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Paul Fitzgerald

Address

MAPrc
Level 4, 607 St Kilda Road,
Melbourne, Victoria
3004

Country

Australia

Phone

+61 3 9076 6552

Fax

[email protected]

Contact person for public queries

Name

Paul Fitzgerald

Address

MAPrc
Level 4, 607 St Kilda Road,
Melbourne, Victoria
3004

Country

Australia

Phone

+61 3 9076 6552

Fax

[email protected]

Contact person for scientific queries

Name

Paul Fitzgerald

Address

MAPrc
Level 4, 607 St Kilda Road,
Melbourne, Victoria
3004

Country

Australia

Phone

+61 3 9076 6552

Fax

[email protected]

No information has been provided regarding IPD availability

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	Exploring alternative rTMS strategies in non-responders to standard high frequency left-sided treatment: A switching study.	2018	https://dx.doi.org/10.1016/j.jad.2018.02.016
Embase	A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.	2019	https://dx.doi.org/10.1002/hbm.24725
Embase	Functional Magnetic Resonance Imaging-Guided Personalization of Transcranial Magnetic Stimulation Treatment for Depression.	2021	https://dx.doi.org/10.1001/jamapsychiatry.2020.3794

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

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