Major Depressive Disorder Clinical Trial
Official title:
Treating Refractory Major Depressive Disorder With Repetitive Transcranial Magnetic Stimulation: A Double-blind, Sham-controlled, Longitudinal Study.
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.
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.
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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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