An Open Label Trial of TMS Therapy for Bipolar Depression
Phase: NA
Conditions: Bipolar Depression
Sponsor: Sheppard Pratt Health System

 
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Protocol Title:   
An Open Label Trial of TMS Therapy for Bipolar 
Depression 
 
 
Funding Agency:  
Philanthropic Funds 
 
 
 
 
Equipment Donation by Neuronetics, Inc. 
 
 
Principal Investigator: 
Scott T. Aaronson, MD 
 
 
 
 
Director, Clinical Research Programs 
 
 
 
 
Sheppard Pratt Health System 
 
 
 
 
6501 N. Charles Street 
 
 
 
 
Baltimore, Maryland 21204 
 
 
Treatment:  
 
Neuronetics Neurostar TMS Therapy® System 
 
 
 
Sheppard Pratt IRB  
Approval Date: 
 
November 18, 2015 
 
 
NCT Number  
 
02640950 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
Objectives……………………………………………………………………..3 
 
Background……………………………………………………………………3 
 
Study Overview & Hypotheses………………………………………………4 
 
Study Design…………………………………………………………………..5 
 
Study Population………………………………………………………………6 
 
Inclusion & Exclusion Criteria………………………………………………..6 
 
Treatment………………………………………………………………………9 
 
Efficacy Measures and Safety……………………………………………….9 
 
Statistical Methods……………………………………………………………11 
 
Informed Consent, Institutional Review Board, 
DSMB, and Regulatory Considerations…………………………………….12 
 
References…………………………………………………………………….14 
 
Appendices…………………………………………………………………….16 
 
List of Tables 
 
Table 1 
 
Schedule of Events: ……………………………………….17 
 
  
 
 
 
 
 
 
 
 

 
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Objectives 
Transcranial Magnetic Stimulation (TMS) is an increasingly accepted 
neurostimulation- based treatment for major depressive disorder.  While there is 
a growing anecdotal database supporting its use in bipolar depression we 
propose to collect open label efficacy and safety data in a small population of 
patients with clinically verified bipolar disorder.  
 
Aims and Hypotheses 
The primary aims of this study are: 
1. To provide clear open-label evidence that a standard course of TMS 
therapy can be effective for patients who have a diagnosis of bipolar 
depression and are currently on mood stabilizing medication. 
2. To investigate the safety of TMS in a population at risk for activation from 
neuromodulation.  In particular to observe if these patients are at risk for 
changing from a depressive state to a mixed or manic state. 
 
Specific Hypotheses are that: 
1. TMS will provide effective antidepressant treatment in patients with bipolar 
depression both type I and II. 
2. TMS will show a shorter time to response in bipolar depressed patients 
compared with the available data in unipolar depressed patients. 
3. TMS can be safely given in bipolar depression without inducing a manic or 
mixed episode switch in patients who are receiving adequate concurrent 
mood stabilizing medication. 
 
Background 
The current FDA approved evidence base for the treatment of bipolar depression 
is limited to three atypical antipsychotics, one of which is paired with an SSRI. 
(Nierenberg et. al. 2015).  The data analyzed from the STEP-BD study supports 
the notion that the use of antidepressants added to mood stabilizers provides no 
improved outcome but may carry the risk of precipitating or supporting a mixed or 
manic episode. (Sachs et. al., 2007, El-Mallakh et. al. 2015) A problem in 
developing safe and effective treatment paradigms for bipolar depression is that 
the population is so heterogeneous and subgroups may require different 
pharmacological interventions (Altshuler et. al. 2003, Goldberg et. al. 2015) 
 
Transcranial magnetic stimulation has had a growing impact on the treatment of 
major depressive disorder.  There is increasing use of this modality as insurers 
have increasingly provided support.  Sheppard Pratt has been a leader in the 
adoption of TMS and our clinical TMS program using the Neuronetics NeuroStar 

 
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TMS Therapy® System (See Appendix 1) has treated over 200 patients over the 
past six years.  While there is a clear evidence base for the use of TMS in MDD, 
there is as yet only a small anecdotal base for its use in bipolar depression 
(Connolly 2012, Nola 2013, Woźniak-Kwaśniewska 2015). 
 
We are currently doing a retrospective look at our experience in treating bipolar 
depression with TMS which has represented about 15% of our patient base. 
(Aaronson data in review) A preliminary evaluation of our database shows that 
we have treated 45 patients with bipolar depression (See Appendix 2). Four 
patients had their course stopped by their clinician due to side effects; none of 
them met the criteria for mania or mixed state.  Five patients had their course 
completed by a different TMS provider (closer to their home) and two had 
incomplete data. For the 34 patients who completed a course of treatment, 26 
(76.5%) met response criteria by Montgomery-Asberg Depression Rating Scare 
(MADRS) score and 12 met remission criteria (35%).  These results are 
numerically superior to our experience in unipolar depression where our 
response rate is 62% and our remission rate is 31%.  In general the treatment 
has been well tolerated and effective.  Most of these patients have a long history 
of either poor efficacy or safety in the use of antidepressants and inadequate 
antidepressant response to the use of mood stabilizers or atypical antipsychotics.   
 
A unique aspect of TMS for the bipolar depression patient is the ability to use the 
neurostimulation during the depressive episode without providing it as a chronic 
intervention as is the case with medication.  The existing database is scant.  
While several trials are listed at clinicaltrials.gov, most of these data have 
remained unpublished.  There is a current multi-center study, that uses the 
Brainsway H-Coil Deep TMS system, but the trial is still enrolling and likely years 
away from publication. 
 
Given that Sheppard Pratt has an active, research based, clinical program, we 
would like to collect data prospectively and formalize diagnostic criteria, outcome 
measures and adverse events for this under-studied population.  We will also be 
collaborating with the Mayo Clinic Rochester site. 
 
Study Overview and Hypotheses  
We propose to screen patients with bipolar depression I or II, who are already on 
acceptable mood stabilization. They may or may not be on antidepressants at the 
time of screening but subjects on antidepressants would be taken off them before 
completing the screening phase.  Those patients who have a depression of at 
least moderate severity without significant symptoms of activation or mania will 
be started on a course of open label TMS treatment of up to 35 sessions.  Safety 
and efficacy assessments will be done weekly.  Patients will complete a course 
of treatment when they meet remission criteria (MADRS score < 10) or at the end 
of 30 treatments, whichever comes first. Patients who are still judged to be 
improving between treatment 25 and treatment 30 will be eligible to complete up 
to five addition treatments as the discretion of each site’s principal investigator. 

 
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Patients who meet response criteria (MADRS score decreases by at least 50%) 
will complete the full course of 30 to 35 TMS sessions.  Patients will be 
withdrawn for safety concerns, particularly the onset of activation suggestive of 
mania or a mixed state. 
 
Patients who meet response or remission criteria will be followed monthly for up 
to six months to evaluate the durability of response.  They will be on standard 
mood stabilizing medications and psychotherapy per their clinician’s discretion. 
 
 
 
The primary study hypotheses are: 
 
1. TMS will provide effective antidepressant treatment in patients with bipolar 
depression both type I and II. 
2. TMS will show a shorter time to response in bipolar depressed patients 
compared with the available data in unipolar depressed patients. 
3. TMS can be safely given in bipolar depression without inducing a manic or 
mixed episode switch in patients who are receiving adequate concurrent 
mood stabilizing medication 
 
The secondary hypothesis is: 
 
1. The majority of treatment responders will show adequate durability of 
response with remitters showing better durability. 
 
Study Design 
Prescreening - Prospective study patients will be prescreened to determine the 
possible presence of bipolar depression and their willingness to be in a treatment 
study.  The PI will introduce the study to the patient and give the patient an IRB- 
approved informed consent to read. The patient will have the opportunity to ask 
any questions about the trial and if desired, may take the consent form home to 
discuss with family, their physician, or others. Those who pass prescreening and 
want be in the study will be scheduled for a screening visit.  
 
The study will be divided into three phases, Screening, Treatment and Follow-up. 
 
Phase I: Screening  
 
At screening all prospective subjects will sign the informed consent. A copy of the 
signed informed consent will be given to each participant. At the time of 
admission to the study, the patient’s current treatment provider, if any, will be 
consulted, with the patient’s permission, about the patient’s participation in the 
study. After informed consent is obtained, patients will be eligible to be screened 
for inclusion in the study.   
 

 
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Screening will consist of several activities designed to validate that patients are 
suffering from bipolar illness, are currently in the depressed phase, and have 
been depressed in the current episode for at least four weeks but not longer than 
three years.  The main screening tool will be the Mini International 
Neuropsychiatric Interview (M.I.N.I.)) (Sheehan 1998). The Montgomery-Asberg 
Depression Scale (MADRS), the Young Mania Rating Scale (YMRS) and the 
Clinical Global Impression of Severity of Illness (CGI-S) rating will be done to 
confirm the patients’ depression level and the absence of mania. As well, 
patients will be evaluated for the presence of any medical or psychiatric 
conditions that would either make it unsafe for them to participate in the trial (i.e., 
an unstable medical condition) or confound evaluation of the course of their 
bipolar condition (i.e., the presence of psychosis, substance abuse, or an eating 
disorder). Please see inclusion and exclusion criteria for specific qualifying 
parameters.  When all inclusion criteria have been met and none of the exclusion 
criteria are present, patients are eligible to enter Phase II.  They will be kept on 
mood stabilizing agents but will be tapered off of antidepressants. .  As part of 
this initial evaluation, the study physician will evaluate the course of each 
subject’s illness to determine the optimal medications to use during the course of 
TMS.  If the subject, the referring physician or the study physician feels that it 
would be unsafe or unwanted to stop the antidepressant medication, the subject 
will be dropped from study participation and returned to routine clinical care.  The 
course of TMS treatment will not start until two weeks after the antidepressant 
has been completed. This phase will last 1 to 28 days in order to accommodate 
possible changes in medication.   
 
The subject’s referring clinician will be advised of their patient’s participation and 
asked not to change medications during the open label TMS treatment. The 
referring clinician will be invited to follow along or transfer care to the study 
physician until the subject completes or discontinues open label treatment, at 
which point care will return to the referring clinician who will be provided with a 
transfer note by the study staff. 
 
Phase II:  Open Label TMS Treatment 
 
Once study patients are on stable medication and it is confirmed that they meet 
the entry criteria for Phase II they will begin a standard course of five times a 
week TMS treatment for six weeks. They will be assessed at each treatment visit 
for side effects, concomitant medication use, and once per week for severity of 
depression and evidence of any symptoms suggestive of mania or agitation. Any 
suggestion of mania or activation will be assessed by the study physician who 
will evaluate to determine if the subject can remain in the study or needs other 
intervention to manage emerging symptoms. 
 
The MADRS, the 17-item Hamilton Depression Rating Scale (HAM-D17), the 
Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR16), the 

 
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YMRS, the C-SSRS (Columbia Suicide Severity Rating Scale) and CGI-S will be 
performed once per week. The CGI-Improvement Scale  
(CGI-I) will be done weekly starting at Visit 3. Treatment will continue until 
remission criteria is reached (MADRS score <10) or 30 treatments have 
occurred, whichever comes first. If improvement is continuing between treatment 
25 and 30, treatments may be extended up to 35. Patients who are discontinued 
due to onset of manic or mixed symptoms will be followed until resolution of 
these symptoms.  Patients who meet response criteria (MADRS score drops by 
at least 50%) or remission criteria will be followed in Phase III.  
 
Phase III: Six Month Follow Up 
 
Patients’ meeting response or remission criteria will be followed monthly for up to 
six months by in-person visits or phone interviews.  The MADRS, CGI-S and 
CGI-I scales will be administered at each encounter. Relapse will be defined as a 
MADRS score of 20 or above for two consecutive weeks.  Patients who meet 
relapse criteria will have an early termination visit the following week and referred 
for standard clinical treatment.   
 
Study Population 
It is estimated that up to approximately 30 patients will participate in the study at 
the Sheppard Pratt site with 20 addition patients enrolling at  the Mayo Clinic 
Rochester site Patients must have Bipolar I or Bipolar II depression as defined by 
the Diagnostic and Statistical Manual of Mental Disorders (DSM-5 criteria) and 
be taking a mood stabilizer acceptable to the principal investigator. They will not 
be allowed to take antidepressant medication.  Their depression must be at least 
moderate in severity without significant symptoms of activation or mania.  
 
Patients treated may come from the Retreat assisted living, outpatient services, 
outpatient practices of local psychiatrists, the Sheppard Pratt day hospital, or 
inpatient units.  Patients enrolled at Mayo Clinic will come from their Mood 
program, Mood Clinic, Inpatient practice and the community. It is unlikely that 
current inpatients will qualify for this study as most of them will have co-
morbidities, psychotic symptoms or mixed presentations which would exclude 
them.    
 
 
 
 
Inclusion and Exclusion Criteria – Phase II 
Patients must meet fulfill all of the following inclusion criteria in order to enter 
Phase II of the study: 
 
1. Must be at least 18 years old. 
 

 
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2. Must meet DSM-5 criteria for bipolar (either I or II) depression by clinical 
interview and M.I.N.I. The duration of the current depressive episode must 
be at least 4 weeks and no longer than 3 years in length. 
 
3. Should have a MADRS score of at least 20 at screening, an YMRS score 
of less than 12 and a CGI score of at least 4. 
 
4. Must have signed the informed consent document and have a level of 
understanding sufficient to provide informed consent and to communicate 
with the investigator and site personnel. 
 
5. Must be on a mood stabilizer acceptable to the study physician which is 
consistent with their diagnosis.  The mood stabilizer must be at a stable 
dose for at least four days before starting TMS treatment. 
 
6. If female of childbearing potential, patients must 
a) have a negative urine pregnancy test at screening, and  
b) not be nursing or planning a pregnancy, and 
c) be on a medically acceptable method of birth control acceptable to the 
principal investigator. 
  
 
Choices of contraception that meet the study requirements are 
• Intrauterine device  
• Hormonal contraception (estrogen-containing birth control pills,  
Vaginal ring, patch, injections or implants) 
• Latex condom with spermicide 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
 
Females of childbearing potential who are abstinent can enroll in the 
study. 
 
Patients will not be enrolled in Phase 2 of the study if they meet any of the 
following exclusion criteria:  
 
1. May not be directly affiliated with Sheppard Pratt Clinical Research 
Programs or be immediate family of Research Programs personnel. 
 
2. Must not have another primary Axis I diagnosis.   
 
3. The subject must not have stopped an antidepressant less than two 
weeks before starting TMS treatment or unable to discontinue 
antidepressant therapy. 
 
4. Should have no previous history of psychosis or substance dependence or 
abuse within the six months prior to Screening 

 
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5. Presence of an Axis II disorder felt by the investigator to potentially 
interfere with study compliance would exclude a potential participant. 
 
6. Should not have prior intolerance of TMS or significant lack of response to 
adequate trials of TMS.  
 
7. Should not have a lifetime history of lack of response to ECT or VNS.  
 
8. Should not have any medical condition likely to interfere with safe study 
participation. 
 
9. Women of child-bearing potential who are not using a medically accepted 
means of contraception when engaging in sexual intercourse are 
excluded, as well as women who are pregnant or breast-feeding. 
 
10. Positive urine screen for any substance of abuse will exclude a patient, 
with the exception of benzodiazepines.   A satisfactory explanation in the 
opinion of the investigator along with a negative repeat screen prior to 
Visit 2 is possibly acceptable. 
 
11. Current suicide risk, as evidenced: 
 
a) It is the judgment of the investigator that the patient may be at risk for 
suicide 
b) The patient has rated a “yes” to question 4 or question 5 on the 
Screening C-SSRS 
c) The patient has attempted suicide within the past 12 months prior to 
Screening. 
 
12. History of head injury, epilepsy or seizure disorder, non-removable 
metallic implants or objects in or around the head. 
 
Inclusion Criteria – Phase III 
Patients who meet MADRS criteria for response or remission will enter Phase III, 
the six month follow-up phase of the study. 
 
Patient Withdrawal 
Patients will be told verbally and in the informed consent that they have the right 
to withdraw from the study at any time without prejudice or loss of benefits to 
which they are otherwise entitled.   
 
 
 
The investigator may discontinue a patient from the study for the following 
reasons: 
 

 
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• Non-compliance with 5-day TMS treatment schedule.  Patients must 
complete at least 4 consecutive days of treatment per week.  
• It is the judgment of the investigator that the patient may be at risk for 
suicide 
• The patient has rated a “yes” to question 4 or question 5 on the C-SSRS 
“Since Last Visit” version 
• Patient meets relapse criteria (MADRS score ≥ 20 for two consecutive 
weeks 
• Onset of manic or mixed symptoms 
• Pregnancy 
• Intercurrent illness, adverse event or any other reason concerning the 
well-being of the patient. 
 
Patients who voluntarily withdraw from the study or who are discontinued from 
the study will be asked to complete an early termination visit. The early 
termination visit will be done one week after study withdrawal. A MADRS and 
CGI will be performed by the investigator.  Patients will be referred back to their 
treating psychiatrist for standard clinical care. 
 
Treatment 
 
Treatment will be done using the Neuronetics NeuroStar TMS Therapy® System.   
This treatment modality was approved by the Food and Drug Administration for 
the treatment of Major Depressive Disorder in 2008.   
 
Neuronetics will be providing supplies so there will be no per use charges for 
patients who are unable to use third party insurance for this study.  All subjects at 
the Sheppard Pratt site will receive TMS treatment at no cost. 
 
Open Label Treatment with TMS 
 
Stimulation will occur over the left dorsolateral prefrontal cortex at 120% 
magnetic field intensity relative to the subject’s resting motor threshold, at 10 
pulses per second for 4 seconds, with an off time, or intertrain interval, of 26 
seconds.  Repositioning of the coil, per the NeuroStar User Manual, and 
prophylactic use of acetaminophen or ibuprofen will be allowed for subjects 
reporting sensations at or near the stimulation site which are uncomfortable or 
painful. During the first week of treatment only, in the event that the subject 
cannot tolerate the treatment at these dose parameters, dose intensity may be 
titrated downward to 110% of the motor threshold, with all other dose parameters 
remaining the same.  Treatment sessions will last for 37.5 minutes (75 trains) to 
provide a total of 3,000 pulses per treatment session.  All qualified study patients 
will receive open label TMS treatment, five times a week for a total of 30 
treatments or until they meet remission criteria. 
 
Rationale for Use of Mood Stabilizers 

 
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The goal is to make this study as naturalistic as possible.  Clinical experience to 
date is that we have not seen TMS treated bipolar patients becoming manic but 
there is some risk of activation.  Patients with bipolar type I will require mood 
stabilization within the clear therapeutic range.  As there is no clear evidence for 
what bipolar II patients require for adequate stabilization, the criteria for adequate 
treatment will be more liberal and patient specific at the discretion of the principal 
investigator. 
 
Concomitant Therapy 
 
In general, concomitant medications with primarily central nervous system 
activity will be kept to a minimum outside of the required mood stabilizing agent.  
All concomitant medications taken during the study will be recorded on the case 
report forms.  Patients will be instructed to contact the investigator or study 
coordinator before taking any new prescribed medications, over-the-counter 
medications or supplements. 
 
Subjects will be allowed to take up to 10 mg of Ambien per night for sleep.  
 
Treatment Compliance 
 
The goal of treatment is: 1) at least four treatments per week and 2) no more 
than 3 consecutive days without a treatment.  Patients unable to adhere to this 
schedule will be discontinued. 
 
Efficacy Measures and Safety Evaluations 
Primary Efficacy Measure: 
 
• Montgomery-Asberg Depression Rating Scale (MADRS) 
 
Change from baseline to endpoint in MADRS total score will be the primary 
efficacy measure.  The MADRS is a widely used rating scale for severity of mood 
related symptoms (Montgomery and Asberg, 1979).  The scale consists of 10 
items and ranges from 0 to 60.  Higher scores denote more severe symptoms.  
The MADRS score (as opposed to the HAMD) is more sensitive to detect 
changes in the psychic rather than physical symptoms of depression. 
 
Secondary Efficacy Measures: 
 
• HAMD-17 
 
The 17-item Hamilton Depression Rating Scale will be used as a secondary 
rating scale.  This scale weights the physical symptoms of depression more than 
the psychic symptoms (Hamilton, 1960). 
 

 
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• QIDS-SR16 
 
The Quick Inventory of Depressive Symptoms-Self Rating is a 16 item scale in 
which patients evaluate the severity of their depression.  It is able to give an 
impression from the patients’ point of view as to whether or not they are 
improved and provides a contrast to the clinician-rated scales (Rush 2003). 
 
• C-SSRS 
 
The C-SSRS is a clinician-administered instrument that assesses suicidal 
ideation (Posner. The “baseline” version of the instrument will be administered at 
the screening visit. The “since-last-visit” version will be administered at all other 
visits. 
• YMRS 
 
The Young Mania Rating Scale is the most often used scale to assess the 
degree of manic symptoms a patient has (Young et al., 1978).  This scale will be 
used to screen out patients in mixed or manic states at enrollment and will be 
used during the trial to assess if the TMS treatment may be inducing mania. 
 
• CGI Severity and CGI Improvement 
 
These are global assessment scales of the severity of a patient’s illness on a 
seven-point scale and degree of change from baseline on a seven-point scale 
(Guy, 1976).  The CGI improvement scale is often the most sensitive marker to 
recognize status change in patients. 
 
Safety Evaluations 
The investigator or his designee is responsible for the medical care of study 
patients during the study.  The investigator remains responsible for following, 
through an appropriate health care option, adverse events that are serious or that 
caused the patient to discontinue before completing the study.  The patient will 
be followed until the event is resolved or explained. 
 
Adverse Events 
 
Prior to enrollment, study site personnel will note the occurrence and nature of 
each patient’s medical condition(s).  During the study, site personnel will again 
note any change in the existing conditions and the occurrence and nature of any 
new adverse events.   
 
If a patient experiences an adverse event after the informed consent is signed, 
but before study drug is given, the event will be noted as a pre-existing condition 
unless the investigator believes that the event may have been caused by a 
protocol procedure. 
 

 
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The Data Safety Management Board (DSMB) and the IRB for this study will 
evaluate all adverse event reports including data from both sites.  
 
Serious Adverse Events 
 
A serious adverse event is defined as any event that:  
 
1. Results in death 
2. Results in initial or prolonged inpatient hospitalization 
3. Is a life-threatening experience (immediate risk of dying) 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital abnormality/birth defect 
6. Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above. 
 
Unexpected adverse drug experiences (those not consistent with current 
package labeling information) will also be reported. 
 
The causality of serious adverse events and unexpected adverse drug 
experiences will be assessed by the investigator(s).  The IRB will be sent a report 
of any serious adverse event or unexpected adverse drug experience within 24 
hours of the event becoming known.  Reports to the DSMB will be handled in the 
same manner. 
 
Statistical Methods 
• Sample Size 
 
We are looking to collect sufficient data to demonstrate the efficacy and safety of 
TMS in bipolar depression.  As this is an open label trial we will aim to treat 30 
patients to achieve a reasonable sample size. 
 
• Primary Efficacy Analysis 
 
The primary outcome measure will be the percentage of patients who respond or 
remit after 30 to 35 treatments.  We will subdivide patients based on the 
diagnosis of either bipolar I or bipolar II to compare effectiveness between those 
groups. 
 
The other primary outcome will be the percentage of patients who meet criteria 
for onset of manic symptoms based on the YMRS.  The patients will also be 
separated based on their diagnostic category.   
 
• Secondary Efficacy Analysis 
 
We will also look at the HAM-D and CGI to see the percentage of patients 
meeting response criteria. 

 
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For the patients meeting remission criteria, we will calculate the number of 
treatments required to achieve remission.  Patients who only meet response 
criteria will be treated for 30 to 35 sessions. 
 
Responders and remitters will also be followed for six months after the final 
treatment to see the durability of response.  Percentage of patients’ meeting 
relapse criteria will be calculated. 
 
Informed Consent, Institutional Review Board, DSMB, and Regulatory 
Considerations 
• Informed Consent 
 
The investigator is responsible for ensuring that the patient understands the risks 
and benefits of participating in the study, including answering any questions the 
patient may have throughout the study and sharing any new information that may 
be relevant to the patient’s willingness to continue his or her participation in the 
trial in a timely manner. 
 
The informed consent document will be used to explain the risks and benefits of 
study participation to the patient in simple terms before the patient is entered into 
the study, and to document that the patient is satisfied with his or her 
understanding of the risks and benefits of participating in the study and desires to 
participate in the study. 
 
The investigator is responsible for ensuring that informed consent is given by 
each patient (legal representatives will not be allowed for this trial).  This includes 
obtaining the appropriate signatures and dates on the informed consent 
document prior to the performance of any protocol procedures and prior to the 
administration of study drug. 
 
• Institutional Review Board (IRB) 
 
The investigator will obtain documentation of IRB approval of the protocol and 
the informed consent.  The IRB reviewing these documents is the Sheppard Pratt 
Institutional Review Board    
 
The investigator will supply the IRB with: 
 
1. Informed consent document. 
2. Relevant curricula vitae 
3. Patient recruitment materials and advertisements. 
 
• Data Safety Monitoring Board 
 
This committee will be composed of three psychiatrists experienced with the 
study population and qualified to serve in an advisory capacity in order to 

 
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evaluate safety and efficacy of the trial.  The safety monitoring board will 
convene every six months or at other times if deemed necessary by the study 
investigator. 
 
 
 
 
• Regulatory Considerations 
 
This study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki and that are consistent with good clinical 
practices and applicable laws and regulations. 
 
The protocol will be submitted to clinicaltrials.gov 

 
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Aaronson Final revised 17 AUG 2017 
Version 4 
 
18 of 18 
Appendices 
 
Appendix 1: NeuroStar TMS Therapy® System Prescribing Information 
 
Appendix 2: Analysis of Clinical Database on the Routine Clinical Care of Bipolar Depression with TMS 
 
Appendix 3: Montgomery-Asberg Depression Rating Scale (MADRS) 
 
Appendix 4: Mini International Neuropsychiatric Interview (M.I.N.I.) Version 6.0 
 
Appendix 5: Young Mania Rating Scale (YMRS) 
 
Appendix 6: Clinical Global Impression of Severity of Illness (CGI-S) 
 
Appendix 7: Clinical Global Impression of Improvement (CGI-I) 
 
Appendix 8: Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Appendix 9: 16-item Quick Inventory of Depressive Symptomatology – Self Report (IDS-SR 16) 
 
Appendix 10: 17- item Hamilton Rating Scale for Depression (HAM-D17) 
 
 
List of Tables 
 
Table 1 
Study Schedule