Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)
Phase: NA
Conditions: Treatment Resistant Depression
Sponsor: Stanford University

Stanford Accelerated Intelligent Neuromodulation 
Therapy for Treatment-Resistant Depression 
(SAINT-TRD) 
NCT03068715 
September 18 2018 
Nolan Williams, Principal Investigator 
Stanford University 
Stanford, California 94305 

January 25 2021 
 
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1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
Repetitive transcranial magnetic stimulation (rTMS) is an established technology as 
therapy for treatment-resistant depression. The approved method for treatment is 10Hz 
stimulation for 40 minutes over the left dorsolateral prefrontal cortex (L-DLPFC). This 
methodology has been very successful in real world situations. The limitation of this 
approach includes the duration of the treatment (approximately 40 minutes per treatment 
session). Recently, researchers have aggressively pursued modifying the treatment 
parameters to reduce treatment times with some preliminary success. This study intends 
to further modify the parameters to create a more rapid form of the treatment and look at 
the change in neuroimaging biomarkers. 
 
b. 
Objectives 
This study would allow the investigators to understand if protocols developed for 4-6 
weeks’ worth of treatment can be compressed over five days. 
 
The primary outcome measure for this study will be change in MADRS score. The 
MADRS is a clinical assessment tool used to rate a patient's level of depression and is the 
standard scale used for depression research studies.  
 
Secondary measures will include functional connectivity change of the  
subcallosal cingulate to the default mode network and within the  
default mode network. 
c. 
Rationale for Research in Humans 
   All transcranial magnetic stimulation treatment studies must be conducted in humans. 
 
2. 
STUDY PROCEDURES 
a. 
Procedures 
We will recruit a total of 60 participants for this trial:  
 
-30 (aged 18-80yo) receiving: intermittent theta burst (iTBS) over L DLPFC (five days 
10x/day)  
-30 (aged 18-80yo) receiving identical sham stimulation over L DLPFC with sham iTBS 
(five days 10x/day)  
 
For this study, we will be using the MagPro double blinded rTMS Research System and 
the randomization occurs within the system such that the control sounds like and utilizes 
the same stimulation parameters as the real TMS.  
 

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This allows for the stimulation to be blinded to the treater and the participant.  
 
Participants will have moderately treatment resistant major depressive disorder as defined 
by a score of >/=20 on the HAMD-17, MADRS and BDI-II scales.   
 
Screening Time-Period:  
 
Patients will undergo a screening time period where their eligibility will be confirmed. 
This may occur any time prior to the baseline time period. Following screening informed 
consent, clinical interviews and behavioral testing will occur at the Stanford Psychiatry 
department. The clinical interview will include a screen for inclusion and exclusion 
criteria, MRI safety, TASS, medical and psychiatric history, neurological exam, urine tox 
screen, pregnancy test, and motor threshold (see Motor Threshold section for details 
below).  
 
Diagnosis will be confirmed with the MINI and/or SCID. We will also request medical 
records to confirm information collected during the screening visit. Patients will be 
staged using the Maudsley staging method and a trained rater will perform: HAMD-21, 
MADRS, ATHF, YMRS and SSI.  
 
Patients will fill out self-reports including the BDI-II and C- SSRS. 
 
Baseline Time-Period:  
 
Baseline visits will be separate from screening visits to confirm stability of symptoms 
(stability is defined as a difference in MADRS score below 30% from screening).  
 
Participants will have an MRI scan in the morning.  
 
Baseline clinical measures (MADRS and HAMD-17) will be performed. In addition, 
patients will fill out the C-SSRS self-report.  
 
Participants will practice using the heart rate monitor that they will be using for the 
remainder of the study.  
 
 
Active Study Time-Period:  
 
iTBS sessions will be scheduled in a 5-day sequence, resulting in a total of 50 sessions 
over 5 days. Participants will receive 10 daily stimulations with active or sham iTBS (see 
double-blinded rTMS system for details below). Each session is separated by a 50-minute 
break. This separation between sessions decreases the risk of associated TMS side effects 
(e.g. irritation from the device, headache).  
 
 

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Follow-up Time-Period:  
 
Patients will have the same clinical assessments as well as MRI scans that were 
completed during the baseline time-period at the immediate post-treatment and 1-month 
post-treatment mark. Heart rate will be measured during these time points.  
 
 
Motor threshold:  
 
Using single pulse TMS, the scalp position of lowest motor threshold for the right first 
dorsal interosseous or abductor pollicis brevis muscles will be determined.  
 
Resting motor threshold (MT) was defined using the Adaptive Pest online algorithm.  
 
 
Double blinded rTMS system:  
 
For this study, we will be using the MagPro double blinded rTMS Research System and 
the randomization occurs within the system such that the control sounds like and utilizes 
the same stimulation parameters as the real TMS. This allows for the stimulation to be 
blinded to the treater and the participant. A third party not otherwise involved in the study 
will hold the blinding codes for the study. Blinding codes will be assigned randomly to 
each patient.  
 
During treatment, the blinding code is entered into the MagPro device and the device 
determines which treatment (Active or sham) to apply. Following the first day of 
treatment, subjects will be asked if they believe they are receiving active or sham 
treatment. This information will be collected to determine the success of the blinding 
procedure.  
 
Blinded Phase:  
 
A Magventure double blind key will be inputted into the Magventure double blind system 
during the blinded study week.  
 
Participants in the active stimulation group will receive intermittent TBS (intermittent 
TBS-1800 pulses/session). They will receive 1800 stimuli of iTBS to left DLPFC per 
session per session.  
 
Participants in the sham stimulation group will receive sham intermittent TBS 
(intermittent TBS-1800 pulses/session). They will receive 1800 stimuli of sham iTBS to 
left DLPFC per session.  
 
The L-DLPFC will be targeted utilizing the Localite neuronavigation system if using the 
Magventure device.  
 

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Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to 
cortical surface distance (see Nahas 2004). Sessions will be delivered using the MagPro 
stimulator, with 3-pulse 50-Hz bursts given every 200ms (at 5 Hz). In the intermittent 
TBS, a 2s train of bursts will be given every 10 s for a total of 570s (1800 pulses) over 
the L DLPFC.  
 
 
Heart Rate Monitors:  
 
We will collect heart rate and heart rate variability measurements at all or some of the 
established time points for the active study in order to assess how aiTBS stimulation 
affects heart rate. Some participants may have to shave areas of their chest in order for 
the heart rate monitor electrodes to stick in place.  
 
Imaging and Biomarkers:  
 
We will acquire MRI scan sequences prior to active study phase, immediately after active 
study phase (1-3 days following final aTBS stimulation), and at one-month post- 
stimulation (between 25-30 days following the final aTBS stimulation). At the acute 
phase, we will acquire structural scans and functional scans at the CNI on the Stanford 
campus.  
 
 
Functional Neuroimaging:  
 
First-level models: We will use a canonical hemodynamic response function (HRF) 
convolved event-related model with temporal and dispersion derivatives to model the 
blood oxygen level dependent (BOLD) in the context of a generalized linear model. 
Separate regressors (convolved with the HRF) will be created for stimulus events in each 
paradigm. Temporal and dispersion derivatives will be treated as regressors of no interest. 
A region of interest (ROI) analysis will be performed using our established methods, to 
identify BOLD-dependent signal change in the dorsolateral prefrontal cortex, subgenual 
cingulate, and default mode network nodes (right, left). Beta values for each ROI will be 
extracted for each subject for regression analyses.  
 
The subjects will undergo an MRI scan of the brain that will require about 1 hour in  
the MRI scanner. A structural MRI scan and an fMRI scan will be done using a 3T 
system at Stanford facilities.  
 
During the scan, subjects will lie on the table in the magnet for 1 hour while the images 
are acquired. Instructions may be given through an auditory system. Subjects will wear 
earplugs and may be fitted for a bite bar to help them to keep their head still during the 
scans; for studies that enroll older adults, a bite bar will not be used so as to 
accommodate participants with dentures. These procedures have been used previously in 
younger and older adults alike, and do not cause undue distress in subjects. Brain images 
will be made using conventional MRI imaging (including functional and diffusion tensor 

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imaging).  
 
Patients will undergo a minimum of 3 scans up to a maximum of 6 scans, each 1 hour in 
length.  
 
Acquisition and data extraction:  
 
Clinical interview ratings will be made by trained study personnel. Individual item scores 
will be recorded and then summed according to symptom cluster and scale definitions.  
 
Outcome measures:  
 
The primary outcome measure for this study will be change in MADRS score. The 
MADRS is a clinical assessment tool used to rate a patient's level of depression and is the 
standard scale used for depression research studies.  
 
Secondary measures will include functional connectivity change of the subcallosal 
cingulate to the default mode network and within the default mode network. Primary 
outcome will be assessed as the change between baseline and immediate post-stimulation, 
with secondary measures to include the change between baseline and immediate post-
stimulation and 1-month post-stimulation.  
 
Other secondary measures include heart rate/heart rate variability and the clinical 
interview assessments, to be performed according to the timeline above, include:  
 
HAMD-17 (Hamilton Depression Rating Scale 17-Item)  
C-SSRS (Columbia Suicide Severity Rating Scale)  
HAMD-6 (Hamilton Depression Rating Scale 6-Item)   
YMRS (Young Mania Rating Scale)  
MADRS (Montgomery-Asberg Depression Rating Scale)  
 
b. 
Procedure Risks 
 
These methods are the least risky because the intervals of stimulation have been shown to 
be appropriate for theta burst stimulation in the motor system with no adverse outcomes. 
 
We don’t anticipate any risk from the procedures themselves, aside from those mentioned 
in section 7a i.  
 
c. 
Use of Deception in the Study 
NA 
d. 
Use of Audio and Video Recordings 

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We will be video and audio record study participants during the consent process and 
clinical assessments conducted with them while enrolled in the study. The video and 
audio recordings will be recorded using Zoom video from an encrypted Stanford owned 
laptop. The recordings will be available for training purposes for study personnel only or 
as otherwise consented to on the consent form. We will not use or distribute the 
recordings to outside personnel or scientific meetings etc. unless directly indicated by the 
participant on the video consent form attached in section 13 
 
e. 
Alternative Procedures or Courses of Treatment 
Participants with insurance could alternatively receive traditional rTMS. 
 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
The participants will have the option of pursuing treatment as usual after the 
study (medications, therapy, traditional rTMS). 
 
g. 
Study Endpoint(s) 
The study will end 6 months after the last participant completes their visit.  
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
 
There is early indication that utilizing theta burst stimulation (TBS), which 
mimics natural brain rhythms, is an effective stimulation method for modulation 
of human cortex (Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005). While 
first utilized in the motor cortex, TBS has been since utilized in the limbic and 
cognitive areas with some early success in treating depression (Chung, Hoy, & 
Fitzgerald, 2015). The benefits of this form of stimulation is that it appears to 
allow for a reduction in the time of treatment while maintaining a similar 
efficacy to traditional 40 min 10Hz rTMS stimulation in an early comparison 
study (Bakker et al., 2015).  
 
It is clear that the dorsolateral prefrontal cortex and specifically the posterior 
middle frontal gyrus is heavily implicated in the pathophysiology of at least 
some depression endophenotypes. In depression, the left DLPFC hypoactivity is 
associated with negative emotional judgment and right DLPFC hyperactivity is 
linked to attentional modulation (Grimm et al., 2008). Additionally, the DLPFC 
is a component of the cognitive control network (CCN) and the modulation of 
this node appears to modulate the CCN. At least four groups have performed 
TBS to the DLPFC where the left DLPFC received iTBS (excitatory) and the 
right received cTBS (inhibitory) (Chung et al., 2015).  

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There is emerging evidence from the motor system that the spacing (or timing) 
between theta burst trains is important in the LTP/LTD. If the train goes on for 
two long without a necessary time interval, there is a reversal of the initial 
direction (LTP or LTD) (Gamboa, Antal, Moliadze, & Paulus, 2010). There has 
been a progression in the literature that if there is approximately an hour of 
spacing in between the theta burst trains, there is an EEG resolution and an 
apparent additive effect of the stimulation towards the desired direction (LTP or 
LTD). There is at least 30 minutes of neurophysiological changes on qEEG after 
theta burst stimulation (Noh, Fuggetta, Manganotti, & Fiaschi, 2012). In a visual 
neglect TBS study, there was a non-linear increase in the duration of stimulation 
effect with the doubling of pulse trains (Nyffeler, Cazzoli, Hess, & Muri, 2009). 
It appears that it is best to separate the pulse trains by one hour (Cazzoli et al., 
2012).  
 
 
b. 
Findings from Past Animal Experiments 
NA 
4. 
DEVICES USED IN THE STUDY 
a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
MagPro X100 by MagVenture 
Description: 
Transcranial Magnetic Stimulation Device with theta 
burst stimulation. 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
The 'traditional 10Hz TMS' is on label and the theta 
burst stimulation is off label. It is the same device for 
both. The Magventure is about to be approved by the 
FDA for depression in 2 weeks. When that happens, 
the 'traditional 10Hz' stimulation will be on label with 
an approved device.The theta burst stimulation is 
minimal risk because the risk of seizure is very low 
(only reported once in literature) and there is no other 
risk other than minimal scalp irritation. We will be 
using an approved device 'off label' stimulation 
parameters which has a lower risk profile than the on 
label approved parameters. 
   
Investigational Device 2 
Name: 
3T UHP MRI 
Description: 
MRI 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
The 3T Ultra-High Performance (UHP) MRI scanner 
from GE is an upgrade to the 3T MR750 which was a 

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commercial FDA-approved system. The UHP system 
utilizes many components from GE's 3T Signa Premier, 
including gradient drivers, power supply, transmit and 
receive system electronics, but uses a higher-
performance gradient coil.  
 
The 3T UHP system is not FDA approved, and is 
subject to the 21 CFR 812 investigational device (IDE) 
regulations as well as 21 CFR 50 and 56. The system 
has been tested by GE according to UL606001-1 and 
also for compliance with IEC 60601-2-33 (ed 3.1) - 
meeting limits and guidelines for peripheral nerve 
stimulation, patient thermal, SAR limit, acoustic noise, 
flammability rating UL94-5VA for safety covers, 
hydrostatic pressure, electrical hazards, dielectric 
strength and pinch point. The MRI scans in this study 
will also utilize operational parameters within FDA 
guidelines for Nonsignificant Risk thus an 
Investigational Device  
Exemption (IDE) from FDA should not be necessary.  
 
In addition, the MR research being conducted requires 
highly specialized software that does not exist in the 
clinical MR market so it is designed and implemented 
by researchers at the CNI. Any such software will be 
considered investigational, will function as a non-
significant risk device, and is subject to the 21 CFR 
812 investigational device(IDE) regulations as well as  
21 CFR 50 and 56. The investigational image 
acquisition software will conform to FDA guidelines 
for MR safety related to heating (SAR), peripheral 
nerve stimulation (dB/dt), and acoustic noise.  
 
 
 
5. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
NA 
 
6. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
We will recruit 60 participants only at Stanford to receive the accelerated theta burst 
protocol.  

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b. 
Age, Gender, and Ethnic Background 
We will recruit 60 participants aged 18-80, all gender and ethnic backgrounds.  
 
c. 
Vulnerable Populations 
 
We will not include children, pregnant women, decision impaired. We will include 
economically/educationally disadvantaged as well as homeless because this may be a 
way for them to receive rTMS treatment. We will include employees and students 
because while rTMS is approved by the FDA, it is not covered by many insurance 
carriers and this would be a way for them to receive treatment. rTMS is a low-risk 
procedure, but we will insure all safety measures are taken for these participants.  
We will not include any patients with shrapnel or any ferromagnetic within the head. 
 
d. 
Rationale for Exclusion of Certain Populations 
Women and minorities are included. Children are not because they are typically excluded 
from rTMS studies.  
 
e. 
Stanford Populations 
 Employees and students may sign up for this study, but we will not include lab 
personnel due to HIPAA.  
 
f. 
Healthy Volunteers  
             NA 
g. 
Recruitment Details 
Patients will be recruited through the outpatient clinic in the Psychiatry 
department at Stanford University, through a database of potential research 
subjects that have consented to contact for future research through the 
Depression Research Clinic and through physician referral. Patients will either 
directly contact the research team for study participation, or they will give 
consent to the referring physician and the physician will communicate directly 
with the study team.  
 
We will also use the Stanford Research Registry to recruit study participants. 
The research registry is a list of individuals who have consented to be contacted 
by researchers at Stanford and at present includes over 1,000 volunteers.  
 

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Flyers, Facebook, Brochures, audio, and social media tools will be used to 
advertise the study and recruit participants. 
 
h. 
Eligibility Criteria 
i. 
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. 
 
ii. 
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. 

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• 
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. 
i. 
Screening Procedures 
Patients will undergo a screening time period where their eligibility will be 
confirmed. This may occur any time prior to the baseline time period. Following 
screening informed consent, clinical interviews and behavioral testing will occur 
at the Stanford Psychiatry department. The clinical interview will include a screen 
for inclusion and exclusion criteria, MRI safety, TASS, medical and psychiatric 
history, neurological exam, urine tox screen, pregnancy test, and motor threshold 
(see Motor Threshold section for details below).  
 
Diagnosis will be confirmed with the MINI and/or SCID. We will also request 

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medical records to confirm information collected during the screening visit. 
Patients will be staged using the Maudsley staging method and a trained rater will 
perform: HAMD-21, MADRS, ATHF, YMRS and SSI.  
 
Patients will fill out self-reports including the BDI-II, QIDS, C-  
SSRS, Life Stressors Questionnaire, Trauma History Questionnaire, and MCMI. 
j. 
Participation in Multiple Protocols 
We will not enroll participants that are involved in any other treatment trial. We 
will coordinate with any ongoing biomarker studies to ensure that the treatment 
follows the biomarker study.  
 
k. 
Payments to Participants 
Payment will be given for participation according to the following schedule and 
amounts (to be paid in full at the end of participation in the study):  
 
We will cover parking costs for the screening visit.  
 
$50 Baseline visit  
$50 Immediate post-treatment visit  
$50 1 month visit  
 
Additional bonuses:  
$100 completion bonus (for not missing any follow-up appointments, completing 
all self-reports, and arriving on time to all study visits)  
 
$125 EEG completion bonus ($25/day for 5 days during blinded treatment week). 
This does not include the optional sleep study EEGs.  
 
Each of the above 3 visits takes ~6 hours to complete (approximately $10 per 
hour). Compensation would not place undue pressure to volunteer for the study.  
 
l. 
Costs to Participants 
None.  
m. 
Planned Duration of the Study 
Approximately 6 months from the last date of participation.  
7. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 

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Mania/hypomania and/or seizure. 
 
Currently, no known cases of either risk in iTBS according to a review in The 
Journal of Nervous and Mental Disease (Rachid 2017).  
 
According to a review published in the International Journal of 
Neuropsychopharmacology, there have been 4 cases of treatment-emergent mania 
induced using rTMS (3 bipolar patients, 1 MDD patient) (Xia et al. 2008).  
 
FDA approved rTMS has a 1:30,000 chance of seizure.  
 
Additionally, the following expected AEs were reported in association with TMS 
in a recent publication (Downar et al, 2018): Headache, nausea, dizziness, fatigue, 
insomnia, anxiety or agitation, back or neck pain, vomiting, tinnitus, migraine 
aura, abnormal sensations, unrelated accidents, and unrelated medical problems 
such as cold and flu.  
 
Citation:  
Downar et al (2018). Effectiveness of theta burst versus high-frequency repetitive 
transcranial magnetic stimulation in patients with depression (THREE-D): a 
randomized non-inferiority trial. The Lancet. 
 
ii. 
Investigational drugs 
NA 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
NA  
iv. 
Procedures 
Mania/hypomania and/or seizure. 
 
v. 
Radioisotopes/radiation-producing machines 
NA 
vi. 
Physical well-being 
Participants will have all measures exerted to reduce the chances of seizure and 
discomfort from stimulation.  
 
vii. 
Psychological well-being 
Participants will be placed in a relaxing environment. We do not anticipate that 
there would be any worsening. 
 

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viii. 
Economic well-being 
Participant's economic well-being may benefit from the intervention, as they may 
receive an intervention that would normally cost thousands of dollars in the clinic 
and is not covered by most insurers.  
 
ix. 
Social well-being 
We would anticipate that particularly the responders that perceived social 
wellbeing would improve. We do not anticipate that there would be any 
worsening.  
 
x. 
Overall evaluation of risk 
Low - innocuous procedures such as phlebotomy, urine or stool collection, no 
therapeutic agent, or safe therapeutic agent such as the use of an FDA approved 
drug or device. 
 
b. 
International Research Risk Procedures 
NA 
c. 
Procedures to Minimize Risk 
 
We will have a trained rTMS treater in the room at all times monitoring for 
changes in level of consciousness. We will eliminate any offending agents 
that may increase risk of seizure.  
Monitoring participants depressive symptoms will allow the identification of 
individuals at risk of suicide and therefore the risk of this occurring can be 
minimized. The patient's psychiatrist will be immediately notified if 
participants show signs of suicidal ideation or display depressive symptoms 
which are worse than baseline (by 5 points on the HAMD compared to the 
HAMD score the patient had before study enrollment. If any study personnel 
believe a participant is at risk, the PI Dr Nolan Williams (a psychiatrist) will 
be notified immediately and an emergency consultation between him and the 
participant will be had. If the PI considers it necessary, the patient will be 
referred for emergency psychiatric treatment.  
 
If any participant displays an increased YMRS score (>/=2 points) on 2 
questions, stimulation will be stopped to prevent any possibility of inducing 
hypomania or mania. If any of the research team or clinical staff believe that 
the participant may be showing signs of hypomania/mania, the YMRS will be 
administered by trained personnel immediately, the researchers will not wait 
until the daily assessments are conducted. 
 
d. 
Study Conclusion 

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The experiment will terminate when the final participant has completed their 
treatment and all data has been analyzed.  
 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
Adverse events, protocol deviations, aggregate data will all be frequently 
reviewed by the monitoring board (PD). 
 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The Protocol Director. 
iii. 
Frequency of DSMB meetings 
NA 
iv. 
Specific triggers or stopping rules 
If there is evidence of significant risk to the participants such as multiple seizure 
events or worsening of psychiatric state in a large majority of the participants.  
 
v. 
DSMB Reporting 
NA 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes. 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
No. 
f. 
Risks to Special Populations 
NA. 
8. 
BENEFITS 
Participants have a good chance of improvement in their mood symptoms as versions of 
this new type of rTMS treatment has already demonstrated consistent efficacy. 
 
9. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health 
Insurance Portability and Accountability Act (HIPAA) and privacy policies of Stanford 
University, Stanford Health Care, and Stanford Children’s Health.