Accelerated Theta Burst Stimulation for Inpatients With Bipolar Disorder
Phase: NA
Conditions: Bipolar Disorder, Manic, Bipolar Disorder I
Sponsor: Stanford University

 
 
Accelerated Theta Burst Stimulation for Inpatients with 
Bipolar Disorder 
 
Protocol Number: 52635 
National Clinical Trial (NCT) Identified Number: NCT04058249 
Protocol Director: Bora Kim, MD 
Protocol Version: 2.0 
September 01, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Protocol Title: Accelerated theta burst stimulation for inpatients with bipolar disorder.  
 
Protocol ID: 52635 
 
 
Principle Investigator: Nolan Williams 
Protocol Director: Bora Kim  
Academic Sponsor: David Spiegel 
Study site: Stanford University  
 
Research Synopsis  
This open-label pilot study aims to establish the safety of an accelerated intermittent theta burst 
stimulation (aiTBS) transcranial magnetic stimulation (TMS) protocol in patients experiencing mania or 
hypomania. aiTBS is an accelerated repetitive transcranial magnetic stimulation (rTMS) protocol in which 
10 sessions of intermittent theta burst stimulation (iTBS) rTMS are given each day over five consecutive 
days. 30 participants will receive aiTBS over the right dorsolateral prefrontal cortex (DLPFC) with the 
Magventure MagPro X100 rTMS system. Their responses to the treatment will be measured with 
assessments measuring manic symptoms (Young Mania Rating Scale [YMRS], Altman Self-rating Mania 
Scale [ASRM],  psychosis (Brief Psychiatric Rating Scale [BPRS]),, depression (Montgomery-Asberg 
Depression Rating Scale [MADRS]), and overall mental illness (Clinical Global Impression scale-Severity 
[CGI-S] and CGI-improvement [CGI-I]). Electroencephalography (EEG) will also be employed to measure 
resting EEG response to aiTBS and effective cortical connectivity via TMS-evoked potential (TEP) response. 
Heart rate variability (HRV) is another potential biomarker of mania/hypomania and has been used as a 
measure of TMS responsiveness in depression (Iseger et al., 2017, 2021). HRV monitoring will be employed 
here to investigate this variable in mania as well. Participants will be treated until they become euthymic, 
as measured by YMRS <7 or up to 5 days, whichever comes first. Our hypothesis is that this treatment will 
be well-tolerated by participants and few to no serious adverse events (SAEs) will occur. 
 
Background and Significance 
Approximately 4.8% of adults will have a bipolar episode each year (Merikangas et al., 2011; Miller, 
Dell’Osso and Ketter, 2014), and standard of care pharmacotherapies have relatively high rates of 
treatment resistance (Gitlin, 2006). This study is motivated by recent findings in the neuromodulation field 
suggesting that high-frequency (HF) rTMS (20 Hz) over the right DLPFC can treat symptoms of acute 
mania/hypomania in bipolar disorder (Grisaru et al., 1998; Saba et al., 2004; Praharaj, Ram and Arora, 
2009; Tee and Au, 2020). An early double-blind controlled trial demonstrated the right DLPFC was superior 
to the left in treating mania in 16 patients (Grisaru et al., 1998). A second open-label study in 8 patients 
confirmed that HF-rTMS over the right DLPFC reduced symptoms of mania (Saba et al., 2004). A 41 patient 
single-blind randomized sham-controlled study further supported this work demonstrating that HF-rTMS 
over the right DLPFC was a well-tolerated and decreased measures of mania compared to the sham group 
(Praharaj, Ram and Arora, 2009). In these trials, patients were treated with standard of care 
pharmacotherapy plus rTMS as with this trial.   
 

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Other recent findings in neuromodulation have demonstrated the effectiveness of accelerated rTMS, TBS, 
and accelerated TBS protocols in mental illness. For example, sham-controlled trials of accelerated 
protocols in depression have demonstrated safety, tolerability, and efficacy (Baeken et al., 2013, 2014, 
2015). Further, iTBS has demonstrated equivalent efficacy to FDA-approved HF-rTMS protocols in 
depression (Li et al., 2014; Blumberger et al., 2018). Lastly, accelerated iTBS (aiTBS) such as aiTBS has not 
only proven safe and tolerable, but has also demonstrated higher response and remission rates for 
treating depression (Williams et al., 2018; Cole et al., 2020). These developments motivate the use of this 
novel and efficacious protocol, aiTBS, in treating other mental illnesses. 
 
This is the first clinical trial investigating the application of aiTBS in bipolar disorder. The rationale for the 
use of aiTBS over the right DLPFC to treat mania is based on the safety, tolerability, and effectiveness of 
HF-rTMS over the right DLPFC in mania/hypomania (Grisaru et al., 1998; Saba et al., 2004; Praharaj, Ram 
and Arora, 2009), and the safety, tolerability, and efficacy of aiTBS in treating depression (Williams et al., 
2018; Cole et al., 2020). Additionally, two cases applying conventional daily iTBS for the treatment of 
mania demonstrated efficacy (Muir et al., 2018).  We expect this study to demonstrate safety, tolerability, 
and efficacy in treating mania and to motivate larger sham-controlled trials in the future. 
 
Public Health Impact: Completion of the proposal will provide evidence supporting a safe, tolerable, and 
effective treatment in a high-risk group of psychiatric inpatients. RTMS will be administered on the 
inpatient psychiatry unit during acute illness: a time point that is both practical and generalizable. This 
treatment has the potential to shorten manic episodes and hospital stay, but may also provide enduring 
effects that prevent future episodes of bipolarity. That is, a rapid-acting anti-mania treatment would 
reduce overall healthcare costs by decreasing length of stay and readmission rates.  
 
Preliminary data: We recently completed our outpatient RCT using aiTBS in which we randomized 32 
participants with highly treatment resistant depression (TRD; Maudsley Staging Method score ≥7) and 
treated 29 subjects. Two subjects withdrew before starting and one subject was excluded after being 
determined to not meet inclusion/exclusion criteria. We observed an extremely high rate of overall 
remission of depression where 86% of individuals experienced remission at some point during the 4 week 
followup period in the active group (12/14, MADRS≤10) versus a very low rate of remission in the sham 
group (13%; 2/15). We found an average reduction of 66% in depression symptoms (MADRS) immediately 
after aiTBS in the active group vs. 6% in the sham group. 10/14 participants showed ≥50% reduction in 
symptoms in active versus 2/15 in sham and 8/14 (57%) remitting from depression after 5 days of aiTBS 
in active versus 0/15 in sham, despite having failed numerous medications and psychotherapy. We 
followed these individuals for 4 weeks and there was a median 65-82% reduction in the MADRS during 
this period. At one month post-aiTBS, 64% of active-group participants continued to be responders and 
43% were still in full remission, despite being 1 month after the last treatment. Mean MADRS remained 
significantly lower than baseline at the one-month follow up. These results provide substantial evidence 
that aiTBS is a safe, rapid-acting, and enduring treatment for mental illness. The outcomes of aiTBS for 
depression motivate us to explore the safety, tolerability, and efficacy of aiTBS in other applications such 
as mania. 
 
The Effects of rTMS on right DLPFC in mania: RTMS over the right DLPFC has demonstrated safety, 
tolerability and efficacy in treating the symptoms of mania (Grisaru et al., 1998; Saba et al., 2004; Praharaj, 
Ram and Arora, 2009; Pathak, Sinha and Praharaj, 2015). Further, two published cases have demonstrated 
efficacy of iTBS protocols in treating mania (Muir et al., 2018). These trials applied a conventional daily 
rTMS treatment schedule. Our aiTBS protocol is unique in that it applies a higher-dosage of rTMS with 
consideration of a modern understanding of spaced learning (Smolen, Zhang and Byrne, 2016; Etkin et al., 

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2019) and advanced targeting (Williams et al., 2018). This accelerated form of iTBS allows for the 
possibility to treat acute mania in the inpatient hospital setting. 
 
 
Important to the present study: 
 
Objectives 
 
Primary objective 
1. To assess the safety and feasibility of active aiTBS in hospitalized patients with bipolar disorder I 
and II as defined by adverse events and study retention rates (measured as actual 
recruitment/recruitment milestones). 
 
Secondary objective: 
1. To determine the preliminary anti-manic efficacy of active aiTBS in hospitalized patients with 
bipolar disorder I and II as measured by a significant reduction in the Young Mania Rating Scale 
(YMRS) from baseline to the immediate post-treatment visit.  
 
Exploratory objectives: 
1. To determine the preliminary anti-manic efficacy of active aiTBS in hospitalized patients with 
bipolar disorder I and II as measured by a significant reduction in the Altman Self-rating Mania 
Scale (ASRM) from baseline to the immediate-post treatment visit. 
2. To determine if higher cortical response to TMS (as measured by resting EEG and TMS-EEG at 
baseline and immediate-post visit) is correlated with the anti-manic effects of aiTBS as measured 
by baseline, daily, and immediate post YMRS assessments.  
3. To determine if an increase in HRV (as measured with a Neuroconn device) from baseline to the 
immediate-post visit is correlated with the anti-manic response to aiTBS as measured by baseline, 
daily, and immediate post YMRS assessments..  
4. To determine the functional connectivity changes in the brain as measured by resting-state 
functional MRI from baseline to immediate-post treatment visit following an aiTBS intervention 
over the right DLPFC in inpatients with bipolar disorder I and II experiencing symptoms of mania. 
 
 
Study Design/Methodology 
 
Phase: This is a Phase II clinical trial. 
 
Trial Design: open-label 
 
Methods to minimize bias: This study will minimize bias via its inclusion and exclusion criteria and the use 
of validated laboratory and interview/self-report measures. Explicit hypotheses and corresponding 
planned statistical analyses, power estimates, careful consideration of potential confounds. All 
experimental details will be reported in a fully transparent manner to support replication.  
 
Dose Escalation: TMS stimulation dose will be individually determined according to 90% rMT plus depth 
correction, and then the aiTBS protocol will be administered with a consistent dose across all participants 
receiving active stimulation of 18,000 pulses/day and 90,000 pulses/course. 
  

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Study Arms: One arm, active open-label 
 
Site(s): Single Site (Department of Psychiatry & Behavioral Sciences, Stanford University) 
 
Name of Study Intervention: Accelerated theta burst stimulation for inpatients with bipolar disorder 
 
Interim Analysis: N/A 
 
Stratification: None planned. 
 
Study Population 
 
We will enroll 30 participants in this open-label active Phase II Trial. The target population is adults of all 
genders and ethnicities who are between 18 and 80 years of age with bipolar affective disorder I or II and 
who are otherwise in good general health. Participants must be without contraindications to Magnetic 
Resonance Imaging (MRI) or transcranial magnetic stimulation (TMS) and must be able to attend all study 
visits.  
 
 
Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Male or female, between the ages of 18 and 80 years at the time of screening. 
2. Able to read, understand, and provide written, dated informed consent prior to screening. 
Proficiency in English sufficient to complete questions and follow instructions during fMRI 
assessments and aiTBS interventions 
3. Stated willingness to adhere to 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 
4. Primary diagnosis of Bipolar I or II Disorder according to the Diagnosis and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5) 
5. Currently experiencing a hypomanic or manic episode according to the criteria defined in the 
Diagnosis and Statistical Manual of Mental Disorders, 5th edition (DSM-5) 
6. YMRS score of ≥12 at screening. 
7. Access to ongoing psychiatric care after completion of the study. 
8. Must be adherent or agreeable to pharmacotherapy per clinical standard of care at screening.  
9. Patients who are in both voluntary and involuntary hold.  
10. In good general health, as evidenced by medical history. 
11. For females of reproductive potential: use of highly effective contraception.  
 
 
 
Exclusion Criteria 
 
1. Currently pregnant or breastfeeding. 

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2. Primary psychiatric condition other than Bipolar I or II Disorder requiring treatment other than 
stable comorbid anxiety disorder. 
3. Diagnosis of Intellectual Disability or Autism Spectrum Disorder  
4. Current moderate or severe substance use disorder or demonstrating signs of acute substance 
intoxication or withdrawal 
5. Active suicidal ideation (defined as an M-SSI > 8)  
6. History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, 
brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant 
head trauma 
7. Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion) 
8. Contraindication to MRI (e.g. ferromagnetic metal in their body) 
9. Treatment with another investigational drug or other intervention within the study period 
10. Any other condition deemed by the PI to interfere with the study or increase risk to the participant 
11. Current unmanageable psychosis that the PI believes would interfere with treatment 
12. Any history of psychosurgery 
13. Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO). 
14. Any other condition deemed by the PI to interfere with the study or increase risk to the 
participant. 
 
The effects of rTMS on the developing human fetus are largely unknown (Eryılmaz et al., 2015). 
Accordingly, we will not be enrolling pregnant women to this study. Women of childbearing potential 
must agree to use adequate contraception (hormonal / barrier method of birth control or abstinence) 
prior to study entry and for the duration of study participation. Females of childbearing-age will have a 
pregnancy test prior to starting the rTMS stimulation course. Should a woman become pregnant or 
suspects she is pregnant while participating in this study, she should inform study staff. 
Participants taking certain psychoactive medications will be assessed for safety by the PI, due to potential 
for increase of seizure risk (Pisani et al., 2002) and change in cortical excitability (Minzenberg and 
Leuchter, 2019).   
 
Individuals older than 80 years of age will be excluded for the following reasons: 
1. Even though the study depth adjusts individuals with greater prefrontal over primary motor 
cortex atrophy, the safety limit is at 120% and some individuals require greater than 120% depth 
adjustment to reach PFC (Kozel et al., 2000; Sabesan et al., 2015). With this, there is evidence of 
reduced efficacy in those individuals with advanced age (Freitas et al., 2011; Abellaneda-Pérez et 
al., 2019).  
2. There is evidence of reduced plasticity in individuals with advanced age with a reduction in the 
duration of the effects of TBS (Freitas et al., 2011; Abellaneda-Pérez et al., 2019) which may 
impact the response to the approach. 
 
Study Interventions:  
 
Active aiTBS Intervention: We have previously discussed this stimulation approach with the FDA and the 
FDA deemed the approach nonsignificant risk (NSR). aiTBS will be delivered similarly to previous aiTBS 
studies (Williams et al., 2018; Cole et al., 2020) using the MagVenture MagPro X100 (Skovlunde, Denmark) 
TMS device equipped with a Cool-B65 A/P coil or Cool D-B80 A/P coil. The right DLPFC target will be 

7 
localized for each participant via Montreal Neurological Institute (MNI) coordinates applied to a T1 
structural MRI using a Localite TMS Navigator (Siddiqi et al., 2020). The right dorsomedial (DM) PFC is an 
emerging potential TMS target in bipolar disorder that may provide mood stabilization. This region may 
be targeted in this study if an anti-manic response to the previously mentioned DLPFC target is not 
observed. Baseline and immediate-post YMRS scores will be used to measure anti-manic response. 
Participants will be treated with 1,800 pulses of iTBS (3-pulse 50-Hz bursts at 5-Hz for 2-second trains, 
with trains every 10 seconds) per session at 90% resting motor threshold and depth-adjustment to the 
MNI target (Nahas et al., 2004). Each session will last 10 min followed by a 50-minute intersession interval. 
Ten sessions will be applied per day (18,000 pulses/day) for 5 consecutive days (90,000 total pulses). 
 
Dosing and administration: We will deliver only active aiTBS intervention via a MagPro X100 
(MagVenture, Skovlunde, Denmark) TMS. The intervention paradigm consists of 10 daily sessions (50 total 
over 5 days) of intermittent theta-burst (iTBS) stimulation (3-pulse 50-Hz bursts at 5-Hz for 2-second 
trains, with trains every 10 seconds), delivered with 50-minute inter-session intervals (10-minute sessions, 
50-minutes in between sessions). Stimulation will be delivered at 90% of the resting motor threshold (with 
depth correction to account for the distance between the scalp and cortex). aiTBS  
protocol will be administered with a consistent dose escalation across all subjects of 18,000 pulses/day 
and 90,000 pulses/course. If participants meet remission criteria before treatment day 5 as measured by 
daily YMRS, participants will not receive further treatments.  
 
The right DLPFC will serve as the target for stimulation, though DMPFC may also be targeted if this initial 
target does not demonstrate efficacy. The intervention target will be located via a Localite TMS Navigator. 
The treater identifies the target in the manner approved by the FDA for the Localite TMS Navigator device. 
  
Study Schedule: 
 
Assessment 
Visit 1 
Visit 2*  
Visit 3-7 
Visit 8 
Screening 
Baseline  Treatment 
Days 
Immediate Post 
Capacity to Consent 
x 
 
  
  
Screening Informed 
Consent 
x 
 
  
  
Demographics 
x 
 
  
  
MRI Safety Screening 
Form 
x 
 
  
  

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TASS 
x 
 
  
  
Medical and Psychiatric  
History 
x 
 
  
  
Urine Analysis 
x  
 
  
  
Inclusion/Exclusion 
Criteria 
x 
 
  
  
MINI 
x 
 
  
  
SCID Overview 
x 
 
  
  
MSSI 
x 
 
 
 
YMRS** 
 
x 
x 
x 
BPRS 
 
x  
x 
x 
CGI 
 
x 
x 
x 
ASRM 
 
x 
x  
x  
MADRS-S 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

9 
Current Medications 
 
x 
x 
x 
Motor Threshold 
 
x 
x 
  
Enrollment/ 
  
x 
  
  
Randomization 
Adverse Events 
  
  
x 
x 
 
 
 
Procedures 
Visit 1 
Screening 
Visit 2 
Baseline  
Visits 3-7 
Treatment Days 
Visit 8 
 Immediate Post 
Obtain MT 
x 
x 
x 
 
Stimulation log (rTMS) 
  
  
x 
  
Resting EEG 
  
x  
  
x 
TMS-EEG 
  
x 
  
x  
T1 MRI 
  
x 
  
x  
Resting state fMRI 
  
x  
  
x  
HRV 
 
x 
x 
x 
 
*for this inpatient TMS study, the screening and baseline visits could occur at the same time and place if 
the potential participant qualifies for the study 

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**A YMRS score of ≥12 is an inclusion criteria for this study. If this score falls below 12 after the 
participant has been enrolled then the YMRS  score will be measured every third treatment, as opposed 
to once per day, for closer monitoring of manic symptoms. If the YMRS score falls below 7, this will be 
recorded as remission and  the TMS treatment will end.  
 
Adverse Event Reporting:  
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may occur during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate electronic case report form (eCRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study psychiatrist will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, study staff will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization. 
 

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AEs will be systematically assessed at the start and end of every study day and will be assessed via the 
following standardized questions that will be asked by research staff:  
● Have you had any difficulty with the study interventions?  
● Have you had any problems or other things bothering you since our last visit?  
● Has anything bothered you enough to...  
○ 
...prevent you from doing anything you had planned? 
○ 
...take a prescription or over-the-counter medication or supplement?  
○ 
...see a medical professional? 
○ 
...modify the treatment of a pre-existing medical condition? 
 
Any positive response(s) to the above questions will be documented electronically as part of an AE form 
on REDCap. Any documented AE will be asked about at each subsequent AE assessment until it resolves 
or through the time frame specified above. In Table 3 above, there is a list of common AEs (Blumberger 
et al., 2018). If an unexpected AE occurs, or if a common AE occurs with severity greater than that 
expected, the participant will be further evaluated by a member of the study team with formal medical 
training. 
 
In addition, although the risk of TMS-induced mania is low (Tee and Au, 2020), it will be monitored using 
the YMRS scale as a solicited event. The scale will be administered at baseline, before each treatment day, 
and the immediate-post visit. The score will be monitored along with input from the inpatient clinical 
team concerning possible worsening of symptoms. 
 
Research staff will be trained to attend to signs of AEs and to report any potential unrelated or unexpected 
AE immediately to the Protocol Director (PD) Jean-Marie Batail.  If AEs occur, appropriate medical and/or 

12 
psychiatric care will be facilitated for the research participant, and recorded in the appropriate electronic 
AE logs on REDCap. As per Stanford IRB requirements, AEs will be reported to the IRB annually. The NIMH 
Program Officer will be informed of any actions taken by the IRB as a result of any AEs within 7 business 
days of notification by the IRB (e.g. study modifications imposed by the IRB). 
 
All subjects will have telephone and email contact information to reach the Principal Investigator and the 
Stanford IRB, in case of any distress or adverse response to rTMS or other components of the study. 
 
An AE or SAE can occur from the time that the subject signs the informed consent form to 7 and 30 days, 
respectively, from the time the subject signed the consent form regardless of relationship to the protocol 
or TMS device. All AEs and SAEs will be recorded on the subject-specific and study wide eCRFs. Signs and 
symptoms will be recorded using standard medical terminology. 
 
The following AE information will be included (when applicable): the specific condition or event and 
direction of change; whether the condition was preexisting (i.e., an acute condition present at the start of 
the study or history of a chronic condition) and, if so, whether it has worsened (e.g., in severity and/or 
frequency); the dates and times of occurrence; severity; causal relationship to the TMS device; action 
taken; and outcome. 
 
Serious adverse event reporting: The PI or his designee will immediately report to the IRB any serious 
adverse event (SAE), whether or not considered study intervention related, including those listed in the 
protocol or investigator brochure, and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are SAEs  (e.g., all-cause 
mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event. In that case, the investigator will immediately 
report the event to the IRB. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems either the event 
is chronic or the participant is stable. Other supporting documentation of the event may be requested by 
the IRB and should be provided as soon as possible. 
 
In case of SAEs, the study investigator will complete an Unanticipated Serious Adverse Event Form and 
submit to the IRB as soon as possible, but no later than 10 working days after the investigator first learns 
of the event. The Investigator will provide all relevant documentation pertaining to an SAE (e.g., additional 
laboratory tests, consultation reports, discharge summaries, postmortem reports, etc.) to the IRB in a 
timely manner. Reports relative to the subject’s subsequent course will be submitted to the IRB until the 
event has subsided or, in case of permanent impairment, until the condition stabilizes.  
 
Designated study staff will be responsible for ensuring that unanticipated problems are reported to the 
IRB in compliance with their requirements for reporting serious and unexpected adverse events. 
Reporting will be conducted in compliance with guidelines specified by the Stanford University Research 
Compliance Office. 
 
Statistical Analysis Plan:  

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Descriptive Statistics: Categorical data will be presented as percentages. Continuous data will be 
presented as means with standard deviations. 
 
Inferential tests: Statistical significance will be set at p<0.05, two-tailed.  
 
Covariates: Baseline demographic and clinical measures will be compared across intervention groups 
using standard statistical methods (i.e., categorical variables compared using Pearson chi square test of 
independence; continuous variables compared using univariate ANOVAs). Characteristics that display 
imbalance at the baseline measure or an association with the dependent variable will be assessed for 
inclusion as covariates in the final models. 
 
Assumption checks: Continuous data will be analyzed using standard linear mixed-effects modeling in line 
with intent to treat analysis principles. If residuals of the standard linear models are non-normally 
distributed (Shapiro-Wilk), then data will be analyzed with generalized linear mixed models with 
Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle 
violations of model assumptions. Autoregressive covariance structure will be used for all analyses except 
for cases in which the models fail to converge or converge on non-real solutions. In these cases, alternate 
covariance structures will be explored until the models converge on real solutions. All post-hoc pairwise 
comparisons will be Bonferroni-corrected for multiple comparisons. 
 
General approach considerations: Primary analysis models will be reported both unadjusted and adjusted 
for significant clinical covariates. All statistical analysis will be conducted using SAS/STAT version 9.4 (SAS 
Institute Inc. 2015. SAS® 9.4 Statements: Reference, Fourth Edition. Cary, NC: SAS Institute Inc.). All 
statistical analyses will be overseen by our biostatistician Dr. Booil Jo, an associate professor in the 
Stanford department of psychiatry and behavioral sciences - Center for Interdisciplinary Brain Sciences 
Research. Dr. Jo holds a PhD in Applied Statistics from UCLA and is a leading expert in statistical analysis 
of mental health research. 
 
Primary Objective: To determine the safety and tolerability of open-label aiTBS in inpatients with bipolar 
disorder I and II as measured by AEs and study retention rates. 
 
Primary hypothesis: Open-label aiTBS will demonstrate high safety and tolerability in psychiatric 
inpatients experiencing acute manic symptoms with no SAEs reported and a study retention rate of 
greater than 90% of anticipated recruitment.  
 
Informed Consent Process:  
 
Consent and other informational documents provided to the participant: Consent forms describing in 
detail the study intervention, study procedures, and risks will be given to all participants. Written 
documentation of informed consent is required prior to starting assessments and study interventions. 
The following consent materials are submitted with this protocol: 
 
Two signed consent forms will be obtained from each participant: (1) Screening consent form and (2) 
Study consent form. These consent forms will be administered electronically using REDCap and with a 
physical copy given to the participant.  

14 
 
Consent procedures and documentation: Informed consent is a process that is initiated prior to the 
individual agreeing to participate in the study and continues throughout the individual’s study 
participation. Consent forms will be IRB-approved and the participant will be asked to read and review 
the document. The study PI or his designee will explain the research study to the participant and answer 
any questions that may arise in a private setting. A verbal explanation will be provided in English of the 
purposes, procedures, and potential risks of the study and of the rights of a research participant. 
Participants will have the opportunity to carefully review the written consent form and ask questions prior 
to signing. The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants will be informed that participation is voluntary, and that they may 
withdraw from the study at any time without interruption to their care. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will be 
conducted and documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
Consenting Processes: There will be two consent forms: one consent for screening procedures, and the 
other for study and enrollment procedures. For the first consent process, the clinical research coordinator 
(CRC) will screen the participant’s eligibility for enrollment in the study. The study PI or physician or their 
designee will consent the participants for the second in-person phase of the consenting process, which 
involves discussing the risks of rTMS and MRI scanning. The participant will be consented in the sequence 
that has been defined by our protocol. 
Education and Informed Consent Process: Consent forms will be Institutional Review Board (IRB)-
approved, and the participant will be asked to read and review the document. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. The 
signature will be electronically obtained as described above. The consent process will start with an 
introductory paragraph that describes the study. This statement will be followed by a description of the 
purpose of the research. The participant will be informed that this is an open-label study in which they 
will certainly receive active treatment. Next, the duration of the study and the procedures involved will 
be described.  
The participant will be notified of the discomforts and risks along with the potential benefits. The 
participant will be notified as to the costs for participation (none) as well as the compensation (none) for 
participation. The participant will be made aware of the research funding source (The Baszucki Brain 
Research Fund). The participant will be given information regarding the fact that their participation is 
voluntary. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. The 
participant will be made aware of alternative options. The participant will then be given contact 
information for asking questions about the study or voicing any potential concerns. The participant will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participant will have the opportunity to discuss the study with his or her family or surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document prior to 
any procedures being done specifically for the study. All participants will be provided a copy of their signed 
consent forms. 
Finally, after reading the experimental subjects’ bill of rights, the participant will be asked for their 
signature in order to consent and give permission to be in the research study. To ensure the participant 

15 
has capacity to consent, as part of this process the study psychiatrist or their designee will complete a 
Capacity to Consent form before the consent form is signed. 
Plan for Review of Consent Document: The signed consent document will be confirmed by the PI or study 
psychiatrist or their designee and will be rechecked by the CRC(s) assigned to this study. 
Documentation of Signed Consent: The Site Screening and Enrollment Logs will be utilized to record the 
consent and screening of all subjects and the outcome of each screening. These logs will provide a 
comprehensive list of all subjects who were screened for eligibility and all participants who enrolled into 
the study. This information will be maintained in our electronic study binder on Stanford Medicine Box 
and electronically in REDCap. All subjects who have consented and screened will be included in this log, 
including screen failures. Subjects will be tracked separately on logs, arranged by their screening or 
enrollment ID number. Each page will be numbered and maintained in these logs in the Study Screening 
Binder and the Study Enrollment Binder, respectively.  
 
Risk/Benefit:  
 
Given the high degree of safety of rTMS (Rossi et al., 2009, 2021), there is a low risk-benefit ratio for this 
intervention. That is, the risks are low and potential benefits are high. rTMS will be performed and 
monitored according to widely accepted principles that maximize safety (Rossi et al., 2009). Based on our 
previous open-label studies (Williams et al., 2018; Cole et al., 2020), many of the research participants 
who receive active aiTBS are likely to achieve rapid improvements in their psychiatric symptoms, with 
associated improvement in their social and occupational functioning with minimal side-effects. 
 
Furthermore, the information gained from this study will inform further optimization and personalization 
of TMS therapy for bipolar disorder I and II. Hence, we believe that the risks associated with this study are 
minimal compared to the knowledge gained. 
 
Study Timeline:  
 
The entire project is estimated to take approximately 24 months, broken down into 20 months of data 
collection and an additional 4 months of analysis. 
 
The total duration for each participant from the time of baseline assessment to study completion is 
approximately 7 days. 
 
 
Data Safety Monitoring:  
 
Safety oversight will be under the direction of the Protocol Director, Bora Kim. All adverse events, protocol 
deviations and reportable information will be tracked on REDcap and reported to the IRB as required. Lab 
personnel will meet at least quarterly to assess safety and efficacy data. 
 
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