Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder

Major Depressive Disorder Clinical Trial

Official title:

Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01515215
• Other study ID #: 040 / 2008
• Status: Completed
• Phase: N/A
• First received: January 18, 2012
• Last updated: October 31, 2016
• Start date: July 2008
• Est. completion date: October 2016

Study information

• Verified date: October 2016
• Source: Centre for Addiction and Mental Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review Committee
• Study type: Interventional

Clinical Trial Summary

Major Depressive Disorder (MDD) is one of the most prevalent mental illnesses in North America, in which 30% - 40% fail to respond to conventional treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to be an effective therapeutic tool for the treatment of MDD. This form of treatment involves a series of magnetic pulses directed to the brain for about 30 minutes. Importantly, such treatment is very safe and well tolerated. However, to date, most treatment studies show modest efficacy due to limitations, including: 1) treatments that are delivered to only one side of the brain; 2) treatment that does not directly target a specific brain region associated with depression; 3) treatments that are of short duration; 4) treatments that are of insufficient intensity; and 5) insufficient understanding of the brain mechanisms responsible for therapeutic effect. This study is designed to directly address all of these limitations, as well as explore brain mechanisms (e.g. cortical excitability) through which treatment is optimized.

Description:

Several studies have demonstrated that rTMS is an efficacious treatment for treatment resistant major depressive disorder (TRD). However, recent meta-analyses, and more recent, large, multi-centre studies, have provided evidence suggesting that rTMS, at best, provides modest therapeutic efficacy compared to sham stimulation.

Several reasons may account for this modest therapeutic effect. First, the majority of these studies involved left-sided treatment alone to the dorsolateral prefrontal cortex (DLPFC), which is a significant limitation when considering that electroconvulsive therapy - another form of brain stimulation used in TRD - has been shown to be less efficacious when used unilaterally, compared to bilaterally.

Second, sub-optimal methods were utilized to target the DLPFC (i.e., '5-cm anterior method'), limiting the treatment potential of what is inherently a targeted form of treatment. In this regard, recent data from the investigators suggests that treatment directly targeting the DLPFC provides enhanced therapeutic efficacy compared to the '5-cm anterior' method.

Third, treatment durations were typically short (i.e., 2-4 weeks). Fourth, stimulation intensity may have been insufficient by not taking into consideration coil-to-cortex distance, which is of particular importance when considering that this parameter may contribute significantly to rTMS-induced antidepressant response. Fifth, there has not been a study that has examined TRD across the lifespan in a way that addresses the differences between older and younger adults. Therefore, the investigators propose to conduct a study evaluating the efficacy of rTMS for TRD that directly addresses all 5 of these major limitations.

This study will compare bilateral rTMS to unilateral rTMS and will involve targeting the DLPFC using cortical co-registration techniques, as well as treatments of optimal duration (i.e., up to 6 weeks) and intensity parameters (i.e., adjusted for coil-to-cortex distance). The use of distance cortical co-registration and adjustment for coil-to-cortex distance addresses the major limitation (lack of stimulation intensity to compensate for age-related prefrontal atrophy) in studies that have examined rTMS in an elderly sample. Preliminary data from this research group provide compelling evidence that rTMS may, indeed, be effective when some of these limitations are optimized in both younger and older adults. Finally, it is also essential that research investigate the mechanisms of therapeutic efficacy, so that increases in understanding can be translated into enhanced treatment. For several reasons, cortical excitability may represent a neurophysiological process through which the therapeutic effects of rTMS are mediated. Recent advances in electroencephalography (EEG) technology now permit direct measurement of excitability from the DLPFC; thus, we are now able to ascertain whether these are mechanisms through which the therapeutic effects of rTMS in TRD are mediated.

Hypotheses:

Hypothesis 1: Treatment with bilateral and high frequency left rTMS (HFL-rTMS) will both result in a greater reduction in 17-item Hamilton Depression Rating Scale (HAM-D17) scores compared to sham rTMS.

Hypothesis 2: Bilateral rTMS will result in a significantly greater number of patients reaching criteria for therapeutic response and remission on the HAM-D17 compared to unilateral or sham rTMS.

Hypothesis 3: An increase of excitability following HFL-rTMS to the left DLPFC (in the case of bilateral rTMS or HFL-rTMS) and a decrease in excitability following low frequency right-rTMS (LFR-rTMS; in the case of bilateral rTMS) to the right DLPFC will mediate the relationship between rTMS and response in TRD. Finally, the induction of gamma activity following rTMS will be associated with improved treatment efficacy.

Hypothesis 4: rTMS will result in improved executive function in patients over age 60 with TRD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: October 2016
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• voluntary and competent to consent

• diagnosis of MDD, as confirmed by the Structured Clinical Interview for the DSM-IV (SCID-IV)

• 18 - 85 years of age

• failed to achieve clinical response, or did not tolerate, at least 2 separate antidepressant trials of sufficient dosage for at least 6 wks

• have a score of 20 or greater on the HAM-D17

• have not had an increase or initiation of any psychoactive therapy in the 4 wks prior to testing

• if a woman of childbearing potential, must be on an effective means of birth control

Exclusion Criteria:

• history of DSM-IV confirmed diagnosis of substance dependence in the last 6 months, or substance abuse in the last month

• concomitant, major, unstable medical or neurologic illness

• history of seizures

• acutely suicidal and/or homicidal

• pregnant

• have metal implants

• history of psychosurgery

• co-morbid diagnosis of borderline and/or antisocial personality disorder. as confirmed by the SCID for Axis II Disorders (SCID-II)

• are currently (or in the past 4 weeks) taking more than 2 mg of lorazepam, or equivalent, daily

• ECT treatment in the current episode

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Depressive Disorder, Treatment-Resistant
• Disease
• Major Depressive Disorder

Intervention

Device:
• Repetitive Transcranial Magnetic Stimulation
Magnetic pulses to specific brain regions. (MagPro X100)

Locations

Country	Name	City	State
Canada	Centre for Addiction and Mental Health	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Centre for Addiction and Mental Health	Ontario Mental Health Foundation

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Degree of Change in HAM-D17 Scores		At weeks 3 and/or 6	No
Secondary	Degree of Change in Montgomery-Asberg Depression Rating Scale Scores		At weeks 3 and/or 6	No
Secondary	Degree of Change in Beck Depression Inventory Scores		At weeks 3 and/or 6	No
Secondary	Degree of Change in Brief Psychiatric Ratings Scale Scores		At weeks 3 and/or 6	No
Secondary	Changes in Cortical Excitability	Assessed via TMS-EEG protocol.	At weeks 3 and/or 6	No

External Links

•   Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching hospital, fully affiliated with the University of Toronto, and a PAHO/WHO Collaborating Centre