Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Repetitive Transcranial Magnetic Stimulation
Intervention type(s): Device
Intervention description(s): Magnetic pulses to specific brain regions. (MagPro X100)
Other intervention name(s): MagPro X100 Series (Magventure A/S, Farum, Denmark)
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Major Depression Disorder; Treatment Resistance; repetitive Transcranial Magnetic Stimulation