Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

Study Overview
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Brief Summary
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This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In a double-blind fashion, half the participants will receive accelerated theta-burst stimulation while half will receive sham treatment.

Detailed Description
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Repetitive transcranial magnetic stimulation (rTMS) is an established therapy for treatment-resistant depression. The approved method for treatment is 10Hz stimulation for 40 min over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been effective in real world situations. The limitations of this approach include the duration of the treatment (approximately 40 minutes per treatment session, 5 days per week, for 4-8 weeks). Recently, researchers have pursued modifying the treatment parameters to reduce treatment times with some preliminary successes. This study aims to further modify the parameters to create a more rapid form of the treatment and look at the change in neuroimaging biomarkers.

Official Title
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Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: Active TBS-DLPFC
* Device: Sham TBS-DLPFC
* Device: Open label TBS-DLPFC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 22 to 80 years of age. Able to provide informed consent. Diagnosed with Major Depressive Disorder (MDD) and currently experiencing a Major Depressive Episode (MDE). Participants may currently be on a stable and adequate dose of SSRI antidepressant therapy. Participants may choose to not be on antidepressant therapy for the study duration, or to be switched from other classes to a medication from the SSRI class. Participants may also have a history of intolerance to at least 2 antidepressant medications. These patients with the intolerance history will not be required to be currently taking an antidepressant medication. Participants must qualify as Moderately Treatment Refractory or High Treatment Refractory using the Maudsley staging method. Meet the threshold on the total HAMD17 score of >/=20 at both screening and baseline visits (Day -5/-14 and Day 0). Meet the threshold on the total MADRS score of >/=20 at both screening and baseline visits (Day -5/-14 and Day 0). Meet the threshold on the total BDI-II score of >/=20 at both screening and baseline visits (Day -5/-14 and Day 0). In good general health, as ascertained by medical history. If female, a status of non-childbearing potential or use of an acceptable form of birth control. The form of birth control will be documented at screening and baseline. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable. Exclusion Criteria: Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study. Female that is pregnant or breastfeeding. Female with a positive pregnancy test at participation. Total HAMD17 score of < 20 at the screen or baseline visits. Total MADRS score of < 20 at the screen or baseline visits. Total BDI-II score of < 20 at the screen or baseline visits. Current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR), with the exception of nicotine dependence, at screening or within six months prior to screening. Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past six months or more). History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening. Considered at significant risk for suicide during the course of the study. Cognitive impairment (as noted by previous diagnoses-including dementia). Has a clinically significant abnormality on the screening examination that might affect safety, study participation, or confound interpretation of study results. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation. Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation. History of positive screening urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, opiates. Current (or chronic) use of opiates. History of epilepsy. History of rTMS exposure. History of any implanted device or psychosurgery for depression. Any history of ECT (greater than 8 sessions) without meeting responder criteria History of shrapnel or metal in the head or skull. Low Treatment Refractory using the Maudsley staging method. History of cardiovascular disease or cardiac event. History of OCD. History of autism spectrum disorder. History of intractable migraine History of independent sleep disorder.

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active TBS-DLPFC<br>The active group will receive theta-burst TMS stimulation. | Device: Active TBS-DLPFC<br>* Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.<br>Device: Open label TBS-DLPFC<br>* All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.<br>|
| Sham Comparator: Sham TBS-DLPFC<br>The sham group will receive sham theta-burst TMS stimulation. | Device: Sham TBS-DLPFC<br>* The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.<br>Device: Open label TBS-DLPFC<br>* All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month Post-treatment. | A ten item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders.The MADRS has an overall score range from 0-60, with higher scores corresponding to higher levels of depression. | Pretreatment (baseline), 1-month post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | A provider administered questionnaire used to assess remission and recovery from depression. The HAMD-17 is a 17-item questionnaire to assess depression severity. Each item is scored from 0-4, with higher scores representing increasing depression severity. | pre-treatment (baseline) to 1-month post-treatment | 
| Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment developed by multiple institutions including Columbia University. Participants were asked a series of 6 yes or no questions. Yes answers indicate more suicidal ideation. Here we report a count of participants with an increase, decrease or no change in suicidal ideation. | Pretreatment (baseline) to immediately post-treatment (day 8). | 
| Change in the Hamilton Rating Scale for Depression (HAM-6) Score | The Hamilton Depression Rating Scale (HDRS, also known as Ham-D) is the most widely used clinician-administered depression assessment scale. The Ham-6 version consists of 6 items assessing for: mood, guilt, general somatic symptoms, work and activities, anxiety and slowness of thought and speech). Each item is scored on a scale of 0 to 4, except for the somatic symptoms item, which is scored 0 to 2. On the HAM-6 there can be a total score of 22. Higher scores represent higher depression severity. Here, we report a count of participants with an overall increase, decrease or no change in total HAM-6 score. Participants with an increase in total score (row 3) would signify a worse outcome than participants with a decrease in total score. | Baseline (pre-treatment) and at 1-month post-treatment | 
| Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | The Hamilton Depression Rating Scale (HDRS, also known as Ham-D) is the most widely used clinician-administered depression assessment scale. The Ham-17 version consists of 17 items assessing for: mood, guilt, general somatic symptoms, work and activities, anxiety and slowness of thought and speech. Each item is scored on a scale of 0 to 4, except for the somatic, sleep and insight items which are scored 0 to 2. On the HAM-17 there can be a total score of 22. Higher scores represent higher depression severity. | Pre-treatment (baseline) to immediately post-treatment (day 8). | 
| Change From Baseline Functional Connectivity to Immediate Post-treatment | We quantified the functional connectivity change between the subcallosal cingulate to the default mode network and within the default mode network using baseline and immediate post-treatment MRI scans. We report below, changes of functional connectivity (Fisher's Z score of Pearson correlation coefficient for each pair of ROIs) from immediately post-treatment (day 8) to baseline. | Pretreatment (baseline) to immediately post-treatment (day 8). | 
| Change From Baseline Functional Connectivity to 1-month Post-treatment | We will assess functional connectivity as seen on resting state fMRI, between the subcallosal cingulate to the default mode network and within the default mode network. We report below, changes of functional connectivity (Fisher's Z score of Pearson correlation coefficient for each pair of ROIs) from post-treatment(1m) to baseline. | Pretreatment (baseline) to 1-month post-treatment | 
| Change in Baseline Heart Rate Variability to 1-month Post-treatment | Heart rate variability measures will be compared pre-treatment and 1-month post-treatment. | Pretreatment to 1-month post-treatment | 
| Change in Baseline Heart Rate Variability to Immediate Post-treatment | Heart rate variability measures will be compared pre-treatment and immediately post-treatment. | Pretreatment to immediate post-treatment (day 8). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transcranial magnetic stimulation, theta burst