Ignite Creation Date:
2024-05-05 @ 4:44 PM
Last Modification Date:
2024-10-26 @ 9:23 AM
Study NCT ID:
NCT00305045
Status:
COMPLETED
Last Update Posted:
2012-01-24
First Post:
2006-03-19
Brief Title:
Treating Refractory Major Depressive Disorder With Repetitive Transcranial Magnetic Stimulation
Sponsor:
Centre for Addiction and Mental Health
Organization:
Centre for Addiction and Mental Health
Study Overview
Official Title:
Treating Refractory Major Depressive Disorder With Repetitive Transcranial Magnetic Stimulation A Double-blind Sham-controlled Longitudinal Study
Status:
COMPLETED
Status Verified Date:
2012-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 electroencephalographyevent related brain potential EEGERP 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 andor 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
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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None