Pilot Accelerated Theta Burst Stimulation in Treatment-Resistant Bipolar Depression
Phase: NA
Conditions: Treatment Resistant Depression
Sponsor: Stanford University

 
Pilot Accelerated Theta Burst in Treatment-Resistant 
Bipolar Depression 
NCT03953417 
February 23, 2023 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
Intermittent theta-burst stimulation (iTBS) is a patterned form of 
repetitive transcranial magnetic stimulation (rTMS), an effective, 
neuromodulatory treatment for refractory major depressive disorder 
(MDD). Accelerated rTMS paradigms have become of increasing clinical 
interest to address the potential limiting factors of dose response 
variability and the burden in weeks of treatment at great financial 
expense. Even with reduced treatment time in iTBS compared with 
standard rTMS (10 mins vs the traditional 40 minutes, respectively), 
there remains a barrier in requiring weeks or months of daily 
treatment sessions for desired response. Our recent pilot data (IRB33797) assessing the 
safety, tolerability, and efficacy of an 
accelerated iTBS protocol has shown a 90% antidepressant response in 
individuals with treatment resistant MDD, over the course of only 5 
days. (Cole et al. American Journal of Psychiatry, 2020). 
 
This study intends to utilize our novel accelerated iTBS (aiTBS) 
treatment approach, titled Stanford Accelerated Intelligent 
Neuromodulation Therapy (SAINT) for symptoms of bipolar treatment 
resistant depression (TRD), while assessing changes in neuroimaging 
biomarkers. 
b. 
Objectives 
1. To determine if bilateral, accelerated intermittent theta-burst stimulation (aiTBS) can 
provide a rapid reduction in depressive symptoms among a group of individuals with 
bipolar depression, that is equivalent to the efficacy of the traditional repetitive 
transcranial magnetic stimulation (rTMS) paradigm for unipolar depression. 
2. To determine if responders to this protocol will have a similar change in functional 
connectivity between the left DLPFC and subgenual anterior cingulate cortex 
(sgACC) after treatment. 

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Page 2 of 16 
 
3. To determine whether similar covariates may operate as potential predictors of 
antidepressant treatment response and durability (time to relapse) in bipolar 
depression. 
 
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 30 outpatient participants for an open label pilot study (aged 18-
80 years old) using intermittent theta burst stimulation (iTBS) over the left dorsolateral 
prefrontal cortex (LDLPFC) and right dorsolateral prefrontal cortex (RDLPFC) (up to 
five days, up to 10x/day) with the MagPro rTMS System. Participants will be required to 
meet diagnostic criteria for Bipolar I or Bipolar II (without psychosis or rapid cycling), in 
a current depressive episode. History related to participant's mood cycle will be obtained 
to ensure treatment is delivered during a depressive cycle which will be expected to span 
beyond the length of the 5-day treatment period based on the participant's most recent 
depressive episode duration. Psychiatric history will be obtained through each 
participant's psychiatric provider records to confirm diagnosis and bipolar symptom cycle 
history, which will be reviewed and confirmed during screening. 
 
Participants will be excluded if they have been hospitalized within the last 6 months due 
to suicidality, depression severity or hypomania. 
 
Participants will be required to have stabilized on medications (including at least one of 
the following as a mood stabilizer Lithium with a level of at least 0.6, Depakote with a 
level of at least 50, or a therapeutic dose of carbamazepine, oxcarbamazepine, or an 
antipsychotic) without dose changes for at least 6 weeks prior to the active study time 
period. 
 
They will be ruled out if they have had a manic episode in the past year or a hypomanic 
episode in the last 6 months. 
 
Participants will be asked to stay on their psychotropic medications for stabilization 
throughout the screening, baseline, and active study time periods. Participants will be 
required to have an established psychiatric prescriber. 
 
We will use an adapted baseline covariate of the Maudsley Staging Method for TRD 
bipolar depression. 
 
The study will have 4 time-periods:  
• 
screening time period  
• 
baseline time period  
• 
active study time period  

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• 
follow-up time period 
 
We will utilize a modified study design version of Williams (2018) 
and Cole et al (2020) 
 
Reference: Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford 
Accelerated Intelligent Neuromodulation Therapy for Treatment Resistant Depression. 
Am J Psychiatry. 2020;177(8):716-726. 
doi:10.1176/appi.ajp.2019.19070720 
 
Study Visit Schedule 
 
Pre-screening  
Screening 
Visit 1 
Remote 
Baseline 
visit2 
Day1-5 
Visit 3-7 
Immediate Post) 
(Tuesday-
Wednesday) 
Visit 8 
Self-reports 
(Post 2,3week) 
Post 4 week 
Visit 10 
Remote visit 
(optional) 
Self-
report(requirement) 
Consent 
Initial screen consent 
Screening 
consent 
Study 
consent 
form 
Capacity 
consent 
 
 
 
 
Clinician Administered Assessments / Scales 
Demographic 
Stanford 
demo 
 
 
 
 
 
Demographic II 
inclusion/exc
lusion 
 
 
 
 
 
Dx 
- 
Psychiatrist 
- 
Tx Hx 
MRI safety 
 
TASS (TMS 
safety) 
BSL-
23(borderlin
e) 
MT 
aTBS 
checklist 
 
 
 
Med & Psych Hx  
Med 
Med & Psych 
Self-report 
Mx review 
Concomitant 
Mx review 
 
 
 

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Hx 
ATHF-current 
ATHF-
lifetime 
 
Concomitan
t Mx review 
 
Depression Sx 
- 
IDS-SR 
Mausley+Tha
se Rush 
 
randomizatio
n 
 
 
 
Mania Sx 
- 
Past 
- 
Current 
- 
Med 
SCID- 
including 
BPD module 
 
MINI 
 
 
 
 
 
Psychotic Sx 
- 
Lifetime 
 
 
UTox 
UPreg 
UTox 
UTox 
 
 
 
 
COVID-19 
screening 
COVID-19 
screening 
COVID-19 
screening 
 
 
Self-questionnaire 
 
 
 
MADRS-S 
 
 
 
 
GAD-7 
 
 
MADRS-S 
 
 
 
 
 
PHQ-8 
GAD-7 
BSS 
 
MADRS-S-
24h 
 
 
 
PHQ-8 
BSS 
 
 
 
 
 
PHQ-8 
MADRS-S 
GAD-7 
BSS 
 
PHQ-8 (2,3w) 
 
 
PHQ-8 
MADRS-S 
 
 
GAD-7 
Clinician rating 
Scanning safety 
MADRS-C 
 
MADRS-C 
HAMD-17 
HAMD-6 
YMRS 
YMRS 
MADRS-C 
 
MADRS-C 
HAMD-17 

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Page 5 of 16 
YMRS 
YMRS 
HAMD-17 
 
YMRS 
Mx 
- 
MS 
- 
SSRI 
- 
SNRI 
- 
TCA 
- 
MAOi 
- 
APx 
- 
AED 
- 
Thyroid 
- 
BB 
- 
Amphetamine 
- 
MPH 
- 
Nonstimulant 
- 
Antianxiety 
- 
Insomnia 
- 
other 
CSSRS 
MSSI 
MSSI 
 
 
 
MSSI 
 
MSSI 
 
 
CGI-S 
 
CGI-S 
CGI-I 
 
CGI-S 
CGI-I 
OTHER Self reports 
 
 
 
 
 
 
 
 
Holmes & 
Rahe Stress 
 
 
 
 
 
 
PSQI 
 
 
 
 
 
 
 
SHAPS 
SHAPS 
 
SHAPS 
 
 
SHAPS 
 
 
 
 
 
 
 
 
 
 
CTQ 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Page 6 of 16 
 
 
 
 
 
 
 
 
 
 
Self-
criticism 
scale 
 
 
 
 
 
Other measure 
 
 
 
 
 
 
 
 
 
 
 
Resting EEG 
 
Resting EEG 
 
 
 
 
 
 
Adverse 
events 
 
 
 
 
 
 
 
HRV 
 
 
 
 
 
 
Resting 
state fMRI 
connectivit
y 
 
Resting state 
fMRI connectivity 
 
 
 
 
 
T1 
anatomical 
 
T1 anatomical 
 
 
 
 
 
DWI 
 
DWI 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
The addition of R-DLPFC iTBS should provide an additional safety measure for the risk 
of hypomanic/manic conversion, although this risk is low. Additionally, all speech 
samples used for analyses will be based on randomly segmented splices of audiotapes; 
further, the 5-minute speech sample requires participants to answer a set of standardized 
questions without any reference to personal information.  
c. 
Use of Deception in the Study 
No deception will be used. 
d. 
Use of Audio and Video Recordings 
Video and Audio Recordings: 

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We will be video and audio recording study participants during the 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 consent form. 
e. 
Alternative Procedures or Courses of Treatment 
Participants with insurance could alternatively receive traditional rTMS, although not all 
insurance companies consider bipolar TRD to be covered under the FDA approved 
guidelines. 
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 be terminated if either:  
a) 6 participants reach hypomania as defined by a score of greater than 10 on the YMRS 
scale or  
b) if 2 participants meet DSM-5 clinical criteria for mania without resolution after 
switching to full right sided DLPFC treatment within 24 hrs.  
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
 Bipolar disorder (BD) is an episodic illness comprised by periods of disabling depressive, 
elevated and/or mixed mood states, affecting approximately 4.8% of adults each year 
(Merikangas, et al., 2011; Miller, Dell'Osso, & Ketter, 2014). Individuals with BD are more 
impacted by symptoms of depression than mania or mixed symptoms; however, antidepressant 
medications remain controversial due to the potential concern of manic or hypomanic conversion 
(Judd et al., 2003; Thase, 2005; Tondo, Isacsson, & Baldessarini, 2003). Compared to the general 
population, individuals with BD are at greater risk to attempt (1:3) and complete (1:20 to 1:40) 
suicide, with a greater risk among those experiencing longer periods of depression than manic 
states (Baldesarini et al., 2006; Leverich et al., 2006). Not only are first line treatments limited in 
BD, but treatment resistance can be up to two times higher when compared to unipolar depression 
(Li et al, 2012; Tondo et al., 2014). Despite some advances in recent decades with the use of 
pharmacologic and psychotherapeutic interventions for bipolar disorder symptoms, few treatment 
modalities allow for both phases of symptom clusters (depressive and mania/hypomania) to be 
treated (Geddes & Miklowitz, 2013). 
 
Repetitive transcranial magnetic stimulation (rTMS) is a safe, neuromodulator clinical tool 
utilized in the treatment of depression, which when applied to the left dorsolateral prefrontal 

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cortex (LDLPFC) has shown to be safe and effective in treating individuals with both unipolar 
and bipolar depression (Rachid, Moeglin & Sentissi, 2017; Rostami, et al., 2017; Tavares et al., 
2017). Additional studies have shown that high frequency rTMS over the RDLPFC is effective in 
treating symptoms of bipolar mania (Grisaru, Chudakov, Yaroslavsky and Belmaker, 1998; 
Praharaj, Ram and Arora, 2009; Saba et al., 2004). Intermittent theta burst stimulation (iTBS) is a 
form of patterned rTMS, recently deemed "non-inferior" to standard rTMS in the treatment of 
unipolar major depressive disorder (MDD) (Blumberger et al., 2018; Chung, Hoy, & Fitzgerald, 
2015). With a significant benefit in reduced treatment time in iTBS (10 minutes daily) compared 
with the standard rTMS treatment time (40 minutes daily) for 4-6 weeks, time constraints, 
transportation, and the financial resources to attend daily sessions over weeks of time remain 
cumbersome limitations (Bakker et al., 2015). Accelerated rTMS has recently been explored to 
determine the safety, tolerability, and efficacy in delivering multiple sessions over fewer days, to 
achieve a similar outcome compared with a standard series of rTMS (Sonmez et al., 2018). 
Reducing treatment time is important not only to reduce the individual time and resource strain, 
but also to address accelerating antidepressant response in more severely depressed individuals, at 
greater risk for suicide. Despite advancements in the clinical use of rTMS for depression, 
individual variation, and extensive burden of resources over time require further development. As 
individuals with bipolar disorder tend to have more treatment resistance with more time in 
depression and at greater risk for suicide, the development of symptom cluster targeting, non-
invasive treatment options are of great importance.  
 
Our recent pilot study utilized prior evidence to further enhance the propensity of antidepressant 
response to iTBS by modifying parameters in pulse spacing, dosage and treatment target location 
(Cazzoli et al., 2012; Fox et al., 2012; Gamboa, Antal, Moliadze, & Paulus, 2010; Noh, Fuggetta, 
Manganotti, & Fiaschi, 2012; Nyffeler, Cazzoli, Hess, & Muri, 2009). Applied in a small pilot 
sample of individuals with unipolar (n=20) and bipolar (n=5) TRD, the use of an accelerated 
iTBS paradigm yielded approximately 90% response and remission rates in depressive symptoms, 
in both unipolar and bipolar TRD patients (Cole et al., Manuscript in preparation). Of the 5 
bipolar TRD patients, all met depression remission criteria within 5 days of treatment, with no 
hypomania/mania conversion observed during treatment or at follow-up. This study aims to 
further explore the use of an adapted accelerated iTBS protocol for bipolar TRD. 
4. 
DEVICES USED IN THE STUDY 
a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
MagPro X100 
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: 
Lucus Center MRI (GE) 

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Page 9 of 16 
Description: 
It is a non-invasive imaging scanner. Some of the radio frequency 
imaging coils, imaging software and devices being used in the scan are 
not approved by the FDA but are similar to counterparts that have been 
approved by the FDA. There are currently no known harmful side-effects 
associated with temporary exposure to the strong magnetic field used by 
MRI scanners. There is a small risk of heating from the cables associated 
with these devices. However, they do not pose a serious risk to the health, 
safety, or welfare of a subject. 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
We will be using the exact same MRI device at the Lucas Center as we 
have been using at the CNI. The CNI is closing for 3 months for 
renovations, and to keep the study moving forward, we will use the same 
device at the Lucas Center. 
Investigational Device 3 
Name: 
3T UHP 
Description: 
It is a non-invasive imaging scanner. Some of the radio frequency 
imaging coils, imaging software and devices being used in the scan are 
not approved by the FDA but are similar to counterparts that have been 
approved by the FDA. There are currently no known harmful side-effects 
associated with temporary exposure to the strong magnetic field used by 
MRI scanners. There is a small risk of heating from the cables associated 
with these devices. However, they do not pose a serious risk to the health, 
safety, or welfare of a subject. 
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 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. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
b. 
We will recruit a total of 30 outpatient participants for an open-label pilot study (aged 18-
80 yo) using bilateral intermittent theta burst stimulation (iTBS) over the left dorsolateral 
prefrontal cortex (LDLPFC) and right dorsolateral prefrontal cortex (RDLPFC) (five 
days, 10x/day) with the MagPro rTMS System.  

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Page 10 of 16 
c. 
Age, Gender, and Ethnic Background 
We will recruit 30 participants ages 18-80, all gender and ethnic backgrounds. 
d. 
Vulnerable Populations 
The patient population will not include children or pregnant women as these individuals 
will not be candidates for psychiatric interventions. The sample will include 
economically/educationally disadvantaged as long as they have a fixed phone number by 
which to be contacted. Employees and students will be included as long as they are not 
lab members (due to HIPAA). 
e. 
Rationale for Exclusion of Certain Populations 
Women and minorities are included. Children are not included because they are typically 
excluded from psychiatric interventions e.g., aTBS and children will not be clinical staff 
numbers.  
f. 
Stanford Populations 
N/A 
g. 
Healthy Volunteers 
N/A 
h. 
Recruitment Details 
Patients will be recruited through the outpatient clinic in the psychiatry department, 
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 have a bipolar pre-screening REDCAP database which we will use to screen 
eligibility. 
 
We will also use the Stanford Research Registry (protocol 25422) 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. 
 
For participants who participate in studies IRB 33797 and IRB 37224, data will be shared 
with studies IRB 33797 and IRB 37224. 
 
Social media platforms such as Facebook will be used, as well as Craigslist. Flyers and 
brochures will be used to recruit as well. 
i. 
Eligibility Criteria 
i. 
Inclusion Criteria 

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1. Participants aged 18yo-80yo with a primary diagnosis of bipolar I or II disorder 
in a current major depressive episode or bipolar affective disorder II in a current 
major depressive episode. 
2. Able to read, understand, and provide written, dated informed consent prior to 
screening. Participants will be deemed likely to comply with study protocol and 
communicate with study personnel about adverse events and other clinically 
important information. 
3. Currently diagnosed with Bipolar Depression, according to the criteria defined in 
the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision (DSM-IV-TR) 
4. Meet the threshold on the total HAMD17 score of >/=20 at screening/baseline. 
5. Not in a current state of mania (Young Mania Rating Scale) or psychosis (MINI) 
6. In good general health, as ascertained by medical history. 
7. Access to clinical rTMS after trial completion 
8. Must have a stable psychiatrist during study enrollment, who confirms diagnosis 
of BPD I or II. 
9. Must be on a mood stabilizer regimen for 6 weeks prior to study enrollment and 
agree to continue this regimen during study period 
10. Meet the threshold on the MADRS, with a total score of >/=20 at 
screening/baseline. 
11. History of ECT intolerance or exposure is permitted. 
12. If traveling from out of town for the study, participants will need to have a 
companion with whom they're staying with while receiving open-label treatment. 
ii. 
Exclusion Criteria 
1. Any structural lesion e.g., structural neurological condition, more subcortical 
lesions than would be expected for age, stroke effecting stimulated area or 
connected areas or any other clinically significant abnormality that might affect 
safety, study participation, or confound interpretation of study results. 
2. Metal implant in brain (e.g., deep brain stimulation), cardiac pacemaker, or 
cochlear implants 
3. History of epilepsy/ seizures (including history of withdrawal/ provoked 
seizures) 
4. Shrapnel or any ferromagnetic item in the head 
5. Pregnancy 
6. Autism Spectrum disorder 
7. 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 
8. Active substance abuse (<1 week) or intoxication verified by toxicology screen--
of cocaine, amphetamines, benzodiazepines 
9. Cognitive impairment (including dementia) 
10. Current severe insomnia (must sleep a minimum of 5 hours the night before 
stimulation) 
11. Current mania or psychosis 
12. Showing symptoms of withdrawal from alcohol or benzodiazepines 
13. IQ<70 
14. Parkinsonism or other movement d/o determined by PI to interfere with treatment 

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Page 12 of 16 
15. Any other indication the PI feels would comprise data. 
16. No access to clinical rTMS after discharge 
17. Active suicidal ideation 
18. A diagnosis of obsessive-compulsive disorder (OCD) 
19. Any history of psycho surgery for depression 
20. Any history of myocardial infarction, CABG, CHF, or other cardiac history 
21. The presence or diagnosis of prominent anxiety disorder, personality disorder or 
dysthymia 
22. History of intractable migraine 
23. Mania in the past year, and/or hypomania in the past 6 months. 
j. 
Screening Procedures 
Participants will be seen in the bipolar research clinic for treatment consultation. At that 
time, standard of care treatments will be offered as well as this protocol. The bipolar 
research clinic screening database will be used to identify potential participants, as for all 
bipolar research clinic studies. 
 
k. 
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. 
l. 
Payments to Participants 
There will be payment given for the Probabilistic Reward Task. The Probabilistic Task is 
a neurocognitive assessment to test motivation in depressed patients. Each participant 
will be paid a total of $72 for participation in the Probabilistic Reward Task at each of the 
3 defined time points above: Baseline visit, Immediate post-treatment follow-up and 1 
month-visit (roughly ~$24/visit for a total of $72 across all 3 visits). Anhedonia, defined 
as the lack of reactivity to pleasurable stimuli, is a common symptom in depression. The 
goal of this task is to determine the degree of blunted reward-response in depressed 
participants. 
 
m. 
Costs to Participants 
No cost to the participant. 
n. 
Planned Duration of the Study 
The estimated duration for screening activities is one day.  
 
The estimated duration for active participation is a maximum of 10 days. The active 
study period includes pre-measurements, 5 stimulation days, and immediate post and 1-
month post-measurements). Following the 1-month follow-up, we will continue 
following patients biweekly for up to 6 months since their last aiTBS treatment. These 
follow-ups will be done via online self-reports until participants are no longer responders. 
 

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The estimated duration for analysis of participant data is 6 months.  
6. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
Potential risks for rTMS includes:  
• 
Mania/hypomania 
• 
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. 
 
Potential risks for MRI include: 
• 
Claustrophobia during MRI 
• 
Localized twitching (not painful) sensation during MRI 
• 
Tinnitus after MRI 
 
The MR magnet will attract some metals and affect some electronic devices. Participants 
must notify the operator of any metal on their bodies (ex. surgical clips, devices, or 
tattoos) to see if they are MRI compatible. 
 
 
ii. 
Investigational drugs 
N/A 
iii. 
Commercially available drugs, biologics, reagents, or chemicals 
N/A 
iv. 
Procedures 
The risks of the rTMS procedure being performed are Mania/hypomania and 
Seizure. 

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Page 14 of 16 
The potential risks for MRI procedures are: 
• 
Exposure to magnetic field of MRI which may possibly lead to a localized 
twitching sensation due to the magnetic field changes during the scan. This is not 
unexpected and should not be painful. 
• 
Dizziness or nausea may occur if you move your head rapidly within the magnet. 
• 
The scanner uses a very strong magnet that will attract some metals and affect 
some electronic devices. These devices include cardiac pacemakers, surgical 
clips and implants that are in or on your body. 
• 
Some of the radio frequency imaging coils, the imaging software and other 
devices being used to perform scans are not approved by the FDA, thus are 
considered experimental in nature. 
• 
Some of the images, words, and sounds presented while you are in the scanner 
will have an emotional content and so could be mildly upsetting to some 
individuals. 
 
v. 
Radioisotopes/radiation-producing machines 
N/A 
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 to promote psychological well-
being. 
viii. 
Economic well-being 
Participant's economic well-being will be looked at for as the participant will be receiving 
an intervention that would normally cost $10,000 and not paid for 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 
N/A 
c. 
Procedures to Minimize Risk 
We will have a trained rTMS treater monitoring for changes in level of consciousness at 
all times. We will eliminate any offending agents that may increase risk of seizure. 

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Page 15 of 16 
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, 
hypomania/mania (increase of 4 or more items by at least 1 point on the YMRS scale) 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 (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 the participant displays an increased YMRS score (>/=2 points) on 2 questions, 
stimulation will be switched to all right sided treatment to prevent any possibility of 
further inducing hypomania or mania. If these symptoms persist or increase to any greater 
degree during that same treatment series, the patient will be treated with Ativan and their 
primary psychiatrist will be contacted by the PI. 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 
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 Study PI and Protocol Director (PD). 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The Principal Investigator and Protocol Director  
iii. 
Frequency of DSMB meetings 
N/A 
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 more than 20% of the participants. 
v. 
DSMB Reporting 
N/A 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 

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Yes 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
No 
f. 
Risks to Special Populations 
N/A 
7. 
BENEFITS 
Participants have a good chance of improvement in their mood symptoms as versions of this new 
type of rTMS treatment have already demonstrated consistent efficacy. Our recent open label 
study included 5 patients with bipolar depression, all of whom remitted with this accelerated 
TMS protocol. As this population was not included in the seminal FDA trials, it could further 
benefit this population who have limited treatment opportunities for bipolar depression 
symptoms. 
8. 
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.