Canadian rTMS Treatment and Biomarker Network in Depression Trial

Study Overview
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Brief Summary
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Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for medically refractory major depressive disorder (MDD). rTMS involves direct stimulation of cortical neurons using externally applied, powerful, focused magnetic field pulses. Dozens of studies and several meta-analyses over the last 15 years have shown that rTMS of the dorsolateral prefrontal cortex (DLPFC) produces statistically significant improvements in MDD, even when medications have failed. However, other possible targets may also yield improvement in symptoms. In an attempt to enhance the therapeutic efficacy of current interventions for TRD, attention has turned to identifying domain-specific biomarkers in hopes of ultimately individualizing and predicting treatment response. Unfortunately, the precise nature of this relationship is less than clear, as reflected by the fact that even now there are no established biomarkers that are used routinely in clinical practice to aid in diagnosis. This study also seeks to examine a comprehensive suite of biomarker measurements (MRI, neurophysiology, and genomics/proteomics) before and after rTMS treatment.

Detailed Description
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rTMS is a Health-Canada- and FDA-approved treatment for treatment-resistant depression (TRD), using focused magnetic field pulses to stimulate brain regions involved in emotion regulation, safely and non-invasively. Though rTMS is often effective where medications or therapy fail, it requires a series of lengthy ( 30-40 min) treatment sessions. A new form of rTMS called theta burst stimulation (TBS) has been shown to have greater effects on neural activity than conventional stimulation, despite requiring as little as 40 s of stimulation. The purpose of this study is to assess the efficacy and tolerability of an accelerated TBS protocol, administered 2 times a day in patients with TRD. In addition, the investigators aim to identify candidate biomarkers from a multimodal suite of neuroimaging, neurophysiologic and molecular measures that are predictors and correlates of response to rTMS treatment.

Official Title
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Canadian rTMS Treatment and Biomarker Network in Depression Trial

Conditions
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Depression

Intervention / Treatment
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* Device: rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: are outpatients are voluntary and competent to consent to treatment have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, single or recurrent are between the ages of 18 and 59 have failed to achieve a clinical response to an adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score for that antidepressant trial of > 3 in the current episode 105,106 OR have been unable to tolerate at least 2 separate trials of antidepressants of inadequate dose and duration (ATHF score of 1 or 2 on those 2 separate antidepressants) have a score > 18 on the HRSD-17 item have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening able to adhere to the treatment schedule Pass the TMS adult safety screening (TASS) questionnaire have normal thyroid functioning based on pre-study blood work. Exclusion Criteria: have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of substance dependence or abuse within the last 3 months have a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump have active suicidal intent are pregnant have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD have failed a course of ECT in the current episode or previous episode have received rTMS for any previous indication due to the potential compromise of subject blinding have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed if participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study clinically significant laboratory abnormality, in the opinion of the one of the principal investigators or study physicians currently take more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant due to the potential to limit rTMS efficacy non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single site rTMS<br>Each treatment session will consist of: 1200 pulses of iTBS over a posterior target location followed by a 60 minute interval, then 1200 pulses of iTBS over an anterior target location. | Device: rTMS<br>* intermittent theta burst stimulation (iTBS)<br>|
| Active Comparator: Dual site rTMS<br>Each treatment session will consist of: 600 pulses of iTBS over the posterior target, followed immediately by 600 pulses of iTBS over the anterior target location followed by a 60 minute interval, then 600 pulses of iTBS over the posterior target, followed immediately by 600 pulses of iTBS over the anterior target location. | Device: rTMS<br>* intermittent theta burst stimulation (iTBS)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 17-item Hamilton Rating Scale for Depression (HRSD-17) Change | Change from baseline to 10 days | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 17-item Hamilton Rating Scale for Depression (HRSD-17) Change | Change from baseline to 30 days | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, treatment resistance, biomarkers, repetitive transcranial magnetic stimulation