The Effects of Stanford Accelerated Intelligent Neuromodulation Therapy on Explicit and Implicit Suicidal Cognition

Study Overview
=================
Brief Summary
-----------------
This study evaluates the effects of an accelerated schedule of theta-burst stimulation, termed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), on the neural networks underlying explicit and implicit suicidal cognition in inpatients with major depressive disorder.

Detailed Description
-----------------
We recently developed a form of neuromodulation termed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). SAINT-induced remission is associated with significant reductions in the functional connectivity of the neural network underlying explicit suicidal cognition (between sgACC-DMN). This project aims to further elucidate the SAINT induced neural network changes underlying explicit suicidal cognition.

Official Title
-----------------
The Effects of Stanford Accelerated Intelligent Neuromodulation Therapy on Explicit and Implicit Suicidal Cognition

Conditions
-----------------
Depressive Disorder, Major, Suicide

Intervention / Treatment
-----------------
* Device: Accelerated theta burst stimulation
* Device: Sham stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, between the ages of 18 and 75 years at the time of screening. Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS treatments. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information. Currently diagnosed with either Major Depressive Disorder (MDD) or Bipolar Affective Disorder II (BAD-II) and meets criteria for a current Major Depressive Episode (MDE) according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5). Medical records confirming a history of moderate to severe treatment-resistance as defined by a score of 7-14 on the Maudsley Staging Method155 (MSM). Endorses clinically significant explicit suicidal cognitions (score ≥ 9 on the M-SSI and score ≥ 6 on the BSS self-report). MADRS and HDRS-17 score of >/=20 at screening (visit 1). rTMS/iTBS naive. Access to ongoing psychiatric care before and after completion of the study. Access to clinical rTMS after hospital discharge. In good general health, as evidenced by medical history. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation. Lifestyle considerations: Abstain from becoming pregnant from the screening visit (Visit 1) until after the final study visit (Visit 9). Abstain from caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 3 hours before the start of each dosing session until after the final TMS session. Abstain from alcohol for 24 hours before the start of each dosing session until after collection of the final MRI. Participants who use tobacco products will be instructed that use of cigarettes will not be allowed during the trial. Exclusion Criteria: Pregnancy The presence or diagnosis of prominent anxiety disorder, personality disorder, or dysthymia Current severe insomnia (must sleep a minimum of 5 hours each night before stimulation) Current mania or psychosis Bipolar Affective Disorder I and primary psychotic disorders. Autism Spectrum disorder or Intellectual Disability A diagnosis of obsessive-compulsive disorder (OCD) Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal. Urine screening test positive for illicit substances. Any history of ECT (greater than 8 sessions) without meeting responder criteria No recent (during the current depressive episode) or concurrent use of a rapid acting antidepressant agent (i.e., ketamine or a course of ECT). History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, unexpected seizure/epilepsy disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma. Untreated or insufficiently treated endocrine disorder. Contraindications to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion) Contraindications to MRI (ferromagnetic metal in their body). 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. Treatment with another investigational drug or other intervention within the study period. Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO) Any other condition deemed by the PI to interfere with the study or increase risk to the participant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will receive either active or sham stimulation to the DLPFC. Patients will be randomized to either condition with a 50:50 chance.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dorsolateral prefrontal cortex<br>The accelerated theta burst stimulation protocol will be applied to the left dorsolateral prefrontal cortex (DLPFC) | Device: Accelerated theta burst stimulation<br>* Participants who are randomly assigned to this group will receive active iTBS (intermittent theta burst stimulation) to the left DLPFC. Stimulation intensity will be standardized at 90% of resting motor threshold (adjusted for cortical depth). Stimulation will be delivered using the Magventure Magpro X100 TMS system.<br>|
| Sham Comparator: Sham stimulation<br>Sham (non-active) stimulation will be applied to the left dorsolateral prefrontal cortex (DLPFC) region | Device: Sham stimulation<br>* Participants who are randomly assigned to this group will receive sham stimulation to the left DLPFC. Sham stimulation will be delivered using the Magventure Magpro X100 TMS system.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the neural network underlying Explicit Suicidal Cognition (ESC) as measured by resting state functional connectivity changes in subgenual anterior cingulate (sgACC) and the default mode network (DMN). | We will assess resting state functional connectivity between sgACC and the DMN and within the DMN using magnetic resonance imaging. | At baseline (day 0) and at post-inpatient treatment completion (day 2-7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the neural network underlying Implicit Suicidal Cognition (ISC) as measured by resting state functional connectivity changes in dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). | We will use resting state functional connectivity of DLPFC to the ACC using magnetic resonance imaging. | At baseline (day 0) and at post-inpatient treatment completion (day 2-7) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
suicidality, neuromodulation, transcranial magnetic stimulation, depression