Accelerated TBS in Late Life Depression

Study Overview
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Brief Summary
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This study is a single-arm, open-label, feasibility trial for the assessment of the clinical effects of a course of accelerated bilateral sequential theta burst stimulation (TBS) for late life depression (LLD). Over approximately 1 year, 30 outpatients at the Centre for Addiction and Mental Health (CAMH) meeting diagnostic criteria for LLD will be recruited and will receive 5 consecutive days (always Monday to Friday) of TBS repetitive transcranial magnetic stimulation (rTMS), administered 8 times daily at approximately 1 hour intervals, with continuous theta-burst stimulation (cTBS) applied to the right dorsolateral prefrontal cortex (DLPFC) followed by left DLPFC intermittent theta-burst stimulation (iTBS). Patients will undergo a series of assessments as well as motor threshold testing to determine the appropriate site and strength of stimulation according to standard methods and then begin treatment.

Detailed Description
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Repetitive transcranial magnetic stimulation (rTMS) is an evidenced based 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. In the most recent generation of randomized controlled trials, rTMS consistently achieves response rates of 50-55% and remission rates of 30-35% in medically refractory MDD patients. rTMS has been shown to be effective and well tolerated for depression in younger and older adults. However, early rTMS studies with older adults were limited by suboptimal stimulation parameters, small sample sizes and insufficient treatment durations. The optimal parameters for rTMS are still in the process of being established, however the most widely-used rTMS protocols apply excitatory, 10 Hz stimulation to the left DLPFC; high frequency left (HFL) or inhibitory, 1 Hz stimulation to the right DLPFC; low frequency right (LFR), or both. Taken together with the reported findings of several other groups, results suggest that accelerated rTMS may be feasible, tolerable, and capable of achieving comparable and potentially better remission rates than longer 20 to 30 day courses. However, all of these studies were small, open-label case series, focused on younger adults.

Official Title
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An Open-label Trial on Accelerated Sequential Bilateral Theta Burst Repetitive Transcranial Magnetic Stimulation in Treatment-resistant Late-life Depression

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: MagPro X100/R30 stimulator equipped with the B70 fluid-cooled coil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are voluntary and competent to consent to treatment are an outpatient are ≥60 years old have a Mini-International Neuropsychiatric Interview (MINI 6.0) confirmed diagnosis of major depressive disorder (MDD), with a current major depressive episode (MDE) have failed to achieve a clinical response to an adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score of > 3 in the current episode or have failed to tolerate two separate trials of an antidepressant have a score > 18 on the Montgomery-Asberg Depression Rating Scale (MADRS) have had no increase or initiation of any antidepressant or antipsychotic medication in the 4 weeks prior to screening Pass the TMS adult safety screening (TASS) questionnaire Exclusion Criteria: have a history of substance dependence or abuse within the last 3 months have a concomitant major unstable medical illness as determined by one of the study physicians have active suicidal intent have a lifetime MINI diagnosis of bipolar I or II disorder, or primary psychotic disorder have current psychotic symptoms have a 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. One of these comorbidities will not be exclusionary if they are not deemed to be primary. have a diagnosis of any personality disorder as assessed by a study investigator to be primary and causing greater impairment than MDD have presumed or probable dementia or clinical evidence of dementia as assessed by a Short Blessed Test score of greater than 10. did not respond to a course of electroconvulsive therapy (ECT) in the current depressive episode have received rTMS in the current episode, patients who have had rTMS in a previous episode would be eligible have a history of a primary seizure disorder or a seizure associated with an intracranial lesion. 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 have a implanted electronic device that is currently function such as a defibrillator currently take more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant 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 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: 60 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
Intervention Model: Single Group Assignment
Interventional Model Description: This study is a single-arm, open-label, feasibility trial for the assessment of the clinical effects of a course of accelerated bilateral sequential TBS for LLD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active rTMS treatment<br>Patients will receive accelerated TBS | Device: MagPro X100/R30 stimulator equipped with the B70 fluid-cooled coil<br>* Subjects will receive 5 consecutive days (always Monday to Friday) of TBS rTMS, administered 8 times daily at 1 hour intervals. Patients will undergo cTBS of the R DLPFC at 110-120% RMT using bursts of 3 pulses at 50 Hz, bursts repeated at 5 Hz for a total of 600 pulses over 40 seconds, followed by iTBS of the L DLPFC at 110-120% resting motor threshold (RMT) using bursts of 3 pulses at 50 Hz, bursts repeated at 5 Hz with a duty cycle of 2 s on, 8 s off for a total of 600 pulses over 3 min 9 s. Participants will be titrated to 110-120% RMT within the first four treatments to aid with tolerability. If patients tolerate the stimulation well, the target will be 120%. Assessments focused on depressive symptoms will be administered at baseline, after final treatment and four weeks post final treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Montgomery-Asberg Depression Rating Scale (MADRS) score | The investigators will assess the effects of accelerated sequential bilateral TBS based on change on the MADRS using an ANCOVA covarying for baseline differences to measure the change at the final time point for each subject. Higher MADRS scores indicates more severe depression. The overall score ranges from 0 to 60. | baseline, last day of treatment (day 5, after the final treatment) and 4 weeks post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in 17 Item Hamilton Rating Scale for Depression (HDRS-17) | The investigators will assess the effects of accelerated sequential bilateral TBS based on change on the HDRS-17 using an ANCOVA covarying for baseline differences to measure the change at the final time point for each subject. Higher HDRS-17 scores indicates more severe depression. The overall score ranges from 0 to 53. | baseline, last day of treatment (day 5, after the final treatment) and 4 weeks post treatment | 
| Changes in Beck Depression Inventory (BDI-II) | The investigators will assess the effects of accelerated sequential bilateral TBS based on change on the BDI-II using an ANCOVA covarying for baseline differences to measure the change at the final time point for each subject. Higher BDI-II scores indicates more severe depression. The overall score ranges from 0 to 63. | baseline, last day of treatment (day 5, after the final treatment) and 4 weeks post treatment | 
| Changes in Beck Suicide Scale for Suicide Ideation (BSS) | The investigators will assess the effects of accelerated sequential bilateral TBS based on change on the BSS using an ANCOVA covarying for baseline differences to measure the change at the final time point for each subject. Higher BSS scores indicates more severe suicidality. The overall score ranges from 0 to 38. | baseline, last day of treatment (day 5, after the final treatment) and 4 weeks post treatment | 
| Changes in General Anxiety Disorder-7 (GAD-7) | The investigators will assess the effects of accelerated sequential bilateral TBS based on change on the GAD-7 using an ANCOVA covarying for baseline differences to measure the change at the final time point for each subject. Higher GAD-7 scores indicates more severe anxiety. The overall score ranges from 0 to 21. | baseline, last day of treatment (day 5, after the final treatment) and 4 weeks post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Resistant Depression, rTMS, Accelerated TBS, Late Life Depression