Treating Refractory Major Depressive Disorder With Repetitive Transcranial Magnetic Stimulation
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional

Summary: 
      Studies exploring the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a
      treatment for refractory major depressive disorder (MDD) have shown significant promise.
      Despite this, several questions regarding the treatment parameters needed to optimize
      efficacy remain. Moreover, there is also a lack of clear understanding as to the therapeutic
      mechanisms involved. For example, several lines of evidence suggest that patients with MDD
      have deficits in cortical inhibition (CI) and that these deficits are key to understanding
      the pathophysiology of this disorder. With this study, we seek to confirm the therapeutic
      potential of an acute course of rTMS for treatment-refractory MDD in a large sample of
      patients. In addition, we will strive to clarify the neurophysiological mechanisms through
      which rTMS exerts its therapeutic effects, using both TMS and electroencephalography/event
      related brain potential (EEG/ERP) measures of neurophysiological activity. Moreover, in this
      study, we intend to investigate the efficacy of a maintenance course of rTMS in an effort to
      prevent symptom recurrence.
    

Detailed description: 
      Major Depressive Disorder (MDD) is one of the most prevalent mental illnesses in North
      America, affecting approximately 4% of Canadians annually. Though a number of effective
      treatments are available, as many as 15% of those diagnosed with a depressive disorder die by
      suicide, 30% fail to respond to treatment and approximately 60% experience a relapse. These
      statistics emphasize the need to optimize treatment response, as well as to understand the
      neurobiological mechanisms mediating MDD, in order to improve therapeutic outcome.

      To date, few alternatives have been available for the treatment of refractory symptoms - one
      alternative is electroconvulsive therapy (ECT); however, this treatment is associated with
      significant side effects, most notably memory impairment. Also, ECT requires the use of a
      general anesthetic, and, thus, is a relatively more invasive procedure with an increased risk
      of complications. In addition, the stigma associated with ECT often limits its widespread
      acceptance as a treatment for depressive symptoms. rTMS has been shown to be an effective
      therapeutic tool for the treatment of several neuropsychiatric disorders, including MDD and
      schizophrenia. In MDD, two types of rTMS treatment protocols have been shown to be effective.
      These include high frequency (10Hz) rTMS applied to the left dorsolateral prefrontal cortex
      (DLPFC) (HFL) and low frequency (1Hz) rTMS applied to the right DLPFC (LFR). More recently,
      preliminary studies combining LFR rTMS with HFL rTMS - in effect, Bilateral rTMS - have shown
      this method to be safe, well-tolerated, and superior to using either stimulation protocol
      alone. However, other studies have demonstrated equivocal efficacy of rTMS treatment for MDD.
      Several methodological limitations, however, have tainted most treatment studies, precluding
      the ability to make definitive conclusions regarding the efficacy of rTMS for MDD. These
      limitations include: 1) small sample sizes; 2) a lack of adequate double-blind conditions; 3)
      a lack of adequate treatment duration; 4) biased randomization; 5) patient heterogeneity; 6)
      a lack of maintenance treatment protocols; 7) an unclear understanding of the parameters
      necessary to optimize treatment; and 8) insufficient understanding of the neurophysiological
      mechanisms mediating the therapeutic efficacy of rTMS treatment.

      With this study, we intend to rectify these methodological limitations by: including a large
      sample of treatment refractory patients, who meet pre-established criteria for treatment
      resistance; excluding patients with comorbid Axis II psychopathology; developing and
      maintaining a randomized and double-blind protocol prior to study initiation; extending
      active rTMS treatment courses; evaluating 2 different treatment protocols; and evaluating
      whether the induction of CI mediates the therapeutic effects of rTMS on depressive symptoms.

      With regard to the latter objective, several lines of evidence support our hypothesis
      regarding a mechanistic role of CI in the therapeutic effects of rTMS. First, ECT-mediated
      increases in EEG slow wave activity (SWA) and cortical GABA in patients with MDD suggest that
      enhanced CI is related to clinical improvement. Second, MDD is a disorder that has been
      associated with deficits in CI. Third, deficits in CI, as indexed through cortical GABA, were
      rectified by supplementing antidepressant medication. In addition, a core deficit in MDD -
      cognitive inhibition - is conceptually related to impaired CI. Cognitive inhibition refers to
      the ability to ignore or inhibit mental events. Those with MDD typically experience a
      pronounced difficulty shifting thoughts away from negative ideas. In fact, impaired cognitive
      inhibition for depressogenic thoughts and information has been proposed as a mechanism and/or
      risk factor underlying the development and maintenance of MDD. Research in our event-related
      potential (ERP) lab has examined the neurophysiological correlates of CI in healthy adults
      and in clinical groups. During the Stroop task, CI is associated with an increased negative
      voltage shift peaking between 400 and 500 milliseconds over the frontocentral region of the
      scalp, with a decreased positivity over the left parietal region, referred to as the N450 or
      N500. The experimental manipulation in the present study is distinct from our ongoing MDD-ERP
      work in that we now have the ability to examine changes in the N450 response following
      anticipated rTMS-induced improvements in CI. Thus, if rTMS does bring about improvements in
      CI, and CI is related to cognitive inhibition, this should be associated with normalization
      of the N450 response in MDD.

      Objectives

        1. To evaluate the efficacy of an acute course of rTMS to treat patients with treatment
           refractory MDD.

        2. To evaluate which stimulus protocol demonstrates superior therapeutic efficacy.

        3. To evaluate whether the induction of CI mediates the therapeutic effects of rTMS for
           treatment refractory MDD.

        4. To evaluate the efficacy of a maintenance course of rTMS, for those who responded to
           rTMS treatment, in preventing the recurrence of depressive symptoms.

        5. To measure whether changes in CI are associated with changes in cognitive inhibition
           related to emotional information, as measured by ERP and the Emotional Stroop Task.

      Hypotheses

        1. In the acute treatment phase, active rTMS will be effective in treating refractory MDD
           compared to sham treatment.

        2. Bilateral and HFL rTMS will be shown to have superior therapeutic efficacy to sham rTMS,
           although Bilateral rTMS will be shown to have superior therapeutic efficacy compared to
           HFL stimulation.

        3. The induction of CI will be shown to mediate the therapeutic effects of rTMS on
           refractory symptoms in patients with MDD.

        4. Biweekly maintenance rTMS will be effective in preventing the relapse of depressive
           symptoms.

        5. Prior to rTMS treatment, patients will exhibit diminished neurophysiological indices of
           cognitive inhibition, as measured by the N450 component of the ERP. If rTMS effectively
           increases CI, this increase should be associated with improvements in cognitive
           inhibition, as measured by normalization of the N450.
    

Intervention name(s): Repetitive Transcranial Magnetic Stimulation
Intervention type(s): Device
Intervention description(s): Magnetic pulses to specified brain structures.
Other intervention name(s): MagPro X100 Series (Medtronic A/S, Copenhagen, Denmark)
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Major Depressive Disorder; Repetitive Transcranial Magnetic Stimulation; Treatment resistance