Major Depressive Disorder Clinical Trial
Official title:
Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder
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.
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.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment
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