Treating Refractory Major Depressive Disorder With Repetitive Transcranial Magnetic Stimulation

2014-08-27 03:45:36 | BioPortfolio


Studies exploring the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for refractory major depressive disorder (MDD) have shown significant promise 1-3. 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 4-7. 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 electroencephalogram/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.


Major Depressive Disorder (MDD) is one of the most prevalent mental illnesses in North America, affecting approximately 4% of Canadians annually 8. Though a number of effective treatments are available, as many as 15% of those diagnosed with a depressive disorder die by suicide 9, 30% fail to respond to treatment 10 and approximately 60% experience a relapse 11. These statistics emphasize the need to optimize treatment response as well as to understand the neurobiological mechanisms mediating MDD 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 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 increased risk of complications. In addition, the stigma that is associated with ECT often limits its widespread acceptance as a treatment for depressive symptoms. Repetitive TMS has been shown to be an effective therapeutic tool for the treatment of several neuropsychiatric disorders including MDD and schizophrenia 1, 12, 13. 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) 1, 12. 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 either stimulation protocol alone. However, other studies have demonstrated equivocal efficacy of rTMS treatment for MDD 14, 15. 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) lack of adequate double-blind conditions; 3) lack of adequate treatment duration; 4) biased randomization; 5) patient heterogeneity; 6) lack of maintenance treatment protocols; 7) an unclear understanding of the parameters necessary to optimized treatment and 8) insufficient understanding of the neurophysiologic 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, by excluding patients with comorbid Axis II psychopathology, by developing and maintaining a randomized and double-blind protocol prior to study initiation, by extending active rTMS treatment courses, by evaluating 2 different treatment protocols and by evaluating whether the induction of CI mediates the therapeutic effects of rTMS on depressive symptoms.

With regards to the later objective, several lines of evidence support our hypothesis regarding a mechanistic role of cortical inhibition in the therapeutic effects of rTMS. First, ECT mediated increases in electroencephalography (EEG) slow wave activity (SWA) and cortical GABA in patients with MDD suggest that enhanced CI is related to clinical improvement 4, 16. Second, MDD is a disorder that has been associated with deficits in CI 17. Third, deficits in CI, as indexed through cortical GABA, were rectified by supplementing antidepressant medication 6. 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 18. Research in our event-related potential (ERP) lab has examined the neurophysiological correlates of cognitive inhibition in healthy adults and clinical groups 19. During the Stroop task, cognitive inhibition 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 19-22. The experimental manipulation in the present study that is distinct from our ongoing MDD-ERP work is the ability to examine changes in the N450 response following anticipated r-TMS 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.


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 cortical inhibition mediates the therapeutic effects of rTMS for treatment refractory major depressive disorder.

4. To evaluate the efficacy of a maintenance course of rTMS in preventing the recurrence of depressive symptoms in patients with MDD who were rTMS responders.

5. To measure whether changes in cortical inhibition are associated with changes in cognitive inhibition for emotional information as measured by ERP and the Emotional Stroop.


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 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 at preventing relapse of depressive symptoms.

5. Prior to rTMS treatment, patients will evidence diminished neurophysiological indices of cognitive inhibition, as measured by the N450 component of the ERP. If rTMS effectively increases cortical inhibition, this should be associated with improvements in cognitive inhibition as measured by normalization of the N450.

Study Design

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


Major Depressive Disorder


Repetitive Transcranial Magnetic Stimulation


Centre for Addiction and Mental Health
M5T 1R8


Active, not recruiting


Centre for Addiction and Mental Health

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:45:36-0400

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