key: cord-0950234-97chqa1d
authors: McGirr, Alexander; Vila-Rodriguez, Fidel; Cole, Jaeden; Torres, Ivan J.; Arumugham, Shyam Sundar; Keramatian, Kamyar; Saraf, Gayatri; Lam, Raymond W.; Chakrabarty, Trisha; Yatham, Lakshmi N.
title: Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression: A Randomized Clinical Trial
date: 2021-03-12
journal: JAMA Netw Open
DOI: 10.1001/jamanetworkopen.2021.0963
sha: 14b5d87d07c11c2c2b803d692451be3889172ac5
doc_id: 950234
cord_uid: 97chqa1d

IMPORTANCE: Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. OBJECTIVE: To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. DESIGN, SETTING, AND PARTICIPANTS: This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. INTERVENTIONS: Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. RESULTS: The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, −1.36 [95% CI, −8.92 to 6.19; P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. CONCLUSIONS AND RELEVANCE: iTBS targeting the LDLPFC is not efficacious in the treatment of acute bipolar depression in patients receiving antimanic or mood stabilizing agents. Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02749006

Protocol-Version-8.1; Date 18 December 2018 7

1. LAY ABSTRACT 8 9

Bipolar Disorder is a common condition that is characterized by periods of mood elevation (mania/hypomania), 10 however periods of depression are more common and severely disabling. Effective treatments exist, however 11 many patients do not experience any benefit from them. Hence novel treatment approaches are required for such 12 patients. Neuromodulation techniques involve selective targeting of brain areas which are promising avenues 13

for such bipolar depressed patients. 14 15

Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective neuromodulatory technique that is 16 effective in major depression. There are preliminary evidences suggesting that it is effective in bipolar 17 depression as well, however this comes from a number of very small studies and is therefore unclear. Another 18 encouraging finding from these very small studies is that rTMS does not appear to increase the risk of switch to 19 mania; however this is also limited by studies involving only small number of patients. 20 21

Given the promising preliminary evidence, we propose to study the efficacy of rTMS in bipolar depression. We 22

will do so using a randomized design in which patients and clinicians will not know whether the patient is 23

receiving daily active iTBS-rTMS or sham-rTMS for four weeks. Our focus is on clinical improvement in 24 depressive symptoms; however we will also look at other aspects such as cognition.

Protocol-Version-8. 

Bipolar disorder is a common condition and a leading cause of global disability 1 . Though characterized by 32 episodes of mania/hypomania, individuals with bipolar disorder suffer a significant portion of their lives with 33 chronic and recurring depressive episodes 2,3 . Indeed, patients are reported to experience symptomatic periods 34

as much as half of their lives with syndromal/sub-syndromal depressive symptoms outnumbering 35 manic/hypomanic symptoms in frequency by a 3:1 ratio 2 . While direct and indirect costs of bipolar disorder are 36 estimated to exceed 70 billion dollars annually in the USA alone 4 , the single greatest cost to society is the 37 tragic loss of life associated with suicide in this population 5 , which tends to be more common during depressive 38

periods.

Regrettably, few proven treatments exist for bipolar depression despite the tremendous burden 6 . Indeed, 41

quetiapine, fluoxetine plus olanzapine, and lurasidone alone or in conjunction with lithium or valproate are the 42 only FDA approved treatments for acute bipolar depression. Despite limited evidence for efficacy, other 43 pharmacological treatments such as mood stabilizers, other atypical antipsychotics, adjunctive antidepressants 44 and stimulants are also used widely. Antidepressants are widely used in conjunction with mood stabilizers 45

despite continued controversy about their efficacy and safety 7-9 . While expert opinion suggests this is safe when 46

following ISBD recommendations of concomitant mood stabilization 10 , their clinical benefit appears to be only 47 modest at the best 11 . Thus, a significant portion of bipolar depressed patients do not respond to or have 48 difficulty tolerating many of these interventions. Adjunctive psychotherapy is beneficial but seldom sufficient 49 for many patients (Parikh et al 2012). 50 51

Thus, novel, safe and effective treatments are urgently needed. Though electroconvulsive therapy (ECT) has 52 long been available and effective, some patients are reluctant to consider ECT due to cognitive side effects and 53

stigma. The neuromodulation technique repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, 54

safe and more acceptable method of stimulating brain parenchyma 12 . This technique is not accompanied with 55 the stigma associated with electroconvulsive therapy, and therefore due to its overall acceptability to patients, 56

rTMS has emerged as a viable treatment option. 57 58

The most common rTMS approaches are to target either the right or left dorsolateral prefrontal cortex (DLPFC), 59

with either high-frequency (≥5Hz) or low-frequency (1Hz) We recently systematically reviewed the literature to identify even small numbers of patients with bipolar 71 disorder included in randomized controlled trials in depression. We were able to identify a total of 181 patients 72 with bipolar depression that had been included in these trials 24 . We found that rTMS was efficacious; however 73 the conclusion is limited because it was based on inclusion of a small number of patients distributed across 74 several trials using different methods and parameters. Thus, the efficacy of rTMS in bipolar depression needs to 75

be assessed in larger randomized controlled trials.

Protocol-Version-8.1; Date 18 December 2018

The objective of the proposed study is to determine the efficacy of rTMS directed to the left dorsolateral 80

prefrontal cortex (DLPFC) in acute Bipolar depression. We propose to study active-iTBS-rTMS and sham-81 rTMS delivered to the DLPFC using a randomized double-blind, sham-controlled design with allocation 82 concealment. Patients with Bipolar Disorder with an acute episode of major depression who have not 83 responded to adequate trials with one of the first line treatments outlined in CANMAT guidelines (i.e. lithium, 84

quetiapine, lamotrigine, lurasidone, fluoxetine plus olanzapine or mood stabilizer plus SSRI or bupropion or 85 lurasidone) will be randomized to receive active iTBS-rTMS or sham-rTMS treatment daily for four weeks (20 86 sessions).

At the conclusion of the blinded phase, any patient that has not responded to the treatment arm to which they 89

were randomized, (response defined as ≥50% improvement in clinician rated depressive symptoms), will be 90 offered 4 weeks of active-iTBS rTMS treatment.

The primary outcome measures will be improvement in acute bipolar depression as measured by change in 93

Montgomery Asberg Depression Rating Scale (MADRS) with iTBS-rTMS as compared to sham treatment 94

group. In addition we will also be looking at  Compared to sham-rTMS, active-iTBS rTMS in acute bipolar depression will not lead to higher 20 rates of seizure.

 Active iTBS rTMS will not be associated with more side effects than sham-rTMS. The study is a randomized double-blind sham-controlled trial of rTMS to the left dorsolateral prefrontal cortex 27

in acute Bipolar patients. After preliminary eligibility screen based on demographic and clinical information 28

obtained, patients will be approached and a full description of the study will be provided. Participants who are 29 interested will then be provided with informed consent, at which point a full characterization of inclusion and 30 exclusion criteria will be completed. All subjects will be assessed by a study clinician with a clinical interview 31 as well as a MINI neuropsychiatric interview to confirm the diagnosis. The treatment history will be reviewed 32

in order to confirm the refractoriness to at least one of the first line treatments outlined in the updated 33

CANMAT guidelines. Prior to initiating rTMS treatment, all subjects will have a MRI to target the left DLPFC 34 and fMRI, EEG and NIRS to study the functional aspects of the brain. Eligible participants will be randomized 35

to receive 4 weeks of either active iTBS-rTMS or sham (scalp stimulation with no magnetic pulse) rTMS 36 treatment once daily on weekdays. In addition, participants will complete cognitive testing prior to the 37 commencement. All participants who have completed rTMS treatment ≥ 15 sessions will complete a second set 38 of MRI, neurocognitive tests, EEG and fNIRS post rTMS treatments. Efficacy, safety and tolerability will be 39 evaluated during daily rTMS treatment and also at screen, baseline, week 2 and post rTMS treatments.

Non-responders, whether they received active-or sham-iTBS for 4 weeks will be offered 4 additional weeks of 42 open-label active iTBS-rTMS. Non-responders who choose to participate in the additional 4 weeks of iTBS-43 rTMS will have clinical assessments at week-6 and week-8. The initial blind will be maintained.

All participants will have a follow up telephone interview two weeks after their last rTMS treatment. 46 47 8. STUDY POPLULATIONS 48 49 100 participants diagnosed with Bipolar with an acute depression will be recruited. Participant will be selected 50 from a pool of subjects that have participated in earlier research studies and have consented for future studies 51 with in the Mood Disorders Center at UBC as well as from outpatients and inpatient units of the Mood 52

Disorders Center at UBC. Recruitment will also occur by referrals from other clinics and online. Patients must 53 meet all of the inclusion criteria and none of the exclusion criteria to be randomized into the study.

Participants must meet all of the following inclusion criteria ( 9. have any significant neurological disorder or insult including, but not limited to: any condition likely to 89 be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, 90

cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma 91

with loss of consciousness for greater than or equal to 5 minutes 92

10. have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump 93

11. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) 94 or any other metal object within or near the head, excluding the mouth, that cannot be safely removed 95

12. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry 96

into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic 97

focus over the duration of the study 98

13. have a clinically significant laboratory abnormality, in the opinion of study physician 99

14. are currently (or in the last 4 weeks) taking lorazepam greater than 2 mg daily (or equivalent) due to the 00 potential to limit rTMS efficacy 01

15. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to 02 cooperate with interview). 03

16. have an exclusion criterion for MRI: Those with a history of cranial, thoracic or abdominal surgery, with 04 pacemakers, artificial joints or other metallic implants will be excluded from the MRI scan. Subjects that 05

have agreed to participate in the MRI portion of the study will be pre-screened for any potential metal 06 fragments in the body (particularly in the orbits) if they have had any history of doing metal work or 07 have been involved in use/deployment of ammunitions/explosives, welding, piping etc). 08 09

Randomization will be computer generated, double-blind random assignment and allocation concealment which 11

will be maintained throughout the study. Patients will be randomly assigned to receive either active iTBS-rTMS 12 or sham-rTMS treatments. 13 14

Randomized subjects will be identified by a unique subject number. There will be no replacement of subjects 16 who withdraw from the study. These procedures will be completed a week prior to beginning the trial 22

 Written informed consent will be obtained.

 All participants will complete a clinical evaluation using the following rating scales, research 24

interviews and laboratory investigations.

o The diagnosis of Bipolar Disorder (BD) will be confirmed using the Mini International 26

Neuropsychiatric Interview (MINI-7). 27

o Current depressive symptoms, suicidal ideation and manic symptoms will be ascertained by o Psychosocial functioning will be assed Sheehan Disability Scale (SDS).

o Clinical laboratory Investigations will be completed.

o Information about concomitant medication use will be obtained.

o A physical examination will be performed.

 Participants who meet all the inclusion criteria and who don't have any exclusion criteria will be 39 randomised to receive either active iTB-rTMS or sham -rTMS 40

 All participants will be completing MRI, prior to the baseline visit, to target the left DLPFC region 41

in the brain and the functional activity will be measured using fMRI and simultaneous EEG-fNIRS.

 An Actical watch will be worn on the non-dominant wrist of all participants, between 43 screening and baseline until the end of treatment, in order to monitor sleep patterns and 44 overall level of activity. 45

 Neurocognitive testing will be conducted by a trained administrator using ISBD-BANC which is 46

shown to be sensitive in identifying deficits in patients with bipolar disorder. 47 48 9.2 Daily visits for rTMS treatments: 49  Participants will have to come in for daily rTMS treatments for four weeks (20 sessions). The visits will 50 occur on weekdays during working hours (9am-4pm). Participants who miss 3 consecutive sessions 51

within a week will be withdrawn.

 Day of Evaluation and Comfort Rating Questionnaires (A & B) will be completed.

 Over all well-being, concomitant medication and adverse events will be reviewed.

 Non-responders, whether they received active iTBS-rTMS or sham rTMS for 4 weeks will be offered 4 55

additional weeks of open-label iTBS-rTMS treatment.

 Participants who complete a minimum of 2 weeks (10 sessions Global Impression Severity and Improvement Scale will be administered during these assessments.

 All participants will be completing additional self-report questionnaires. 67 Clinical scales and questionnaires: Clinical and medical information will be supplemented by patient 94 interviews using standardized probes and forms. A 17-item Hamilton Rating Scale for Depression (HAMD-17) 95

will be used to measure current depressive symptoms and manic symptoms will be captured using Young Mania 96

Rating Scale (YMRS). In addition, Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory 97

of Depressive Symptomatology-Self Rated (QIDS-SR), Generalized Anxiety Disorder 7-item scale (GAD-7), 98

and Brief Illness Perception Questionnaire (BIPQ) will be administered. Psychosocial functioning will be 99 captured using a Lam Employment Absence and Productivity Scale (LEAPS) and Sheehan Disability Scale 00

(SDS). The visual analog scale (VAS) will be used to capture overall wellbeing. 01 02

Concomitant Treatment: Participants will be allowed to remain on their psychotropic medications as along as 03 the doses have been stable for at least 2 weeks prior to entering the double blind phase. No changes to 04 psychotropic medication are allowed during the double blind phase. The only variation in psychotropic 05 medication that will be considered is zopiclone (up to 15mg per day) or an equivalent for insomnia. 06 07

Current medications including OTC medications, herbal remedies, homeopathic preparations, and health and 08 dietary supplements taken by the subject within the previous 30 days will be recorded 09 10

Participants must not (or in the last 4 weeks) take more than 2 mg daily (or equivalent) of lorazepam due to the 11 potential to limit rTMS efficacy. If participants are unsure they will be asked to discuss with the investigator 12 before starting the treatment.

Vital Sign Measurement: Vital signs will be obtained at screen, baseline visit, week-2 and post rTMS 15

treatments. Blood pressure will be measured after the subject has been supine for 5 minutes. An Actical Watch is an accelerometer device that records motion. The device does not capture any 19 location or other personal data. The device is pre-loaded with participant unique study ID, age, weight 20 and height, but otherwise contains no personal information. After use and collection of data, these data 21 are downloaded to a secured password-protected laptop. The Actical watch will be worn on the non-22

dominant wrist of all participants between screening and baseline until the end of treatment. The 23

outcome measure of the Actical is to monitor participants sleep patterns and overall level of activity. This will 24

provide information on whether rTMS has an influence on sleep patterns and the timeline of any potential 25 impact. Also, the level of activity will allow monitoring of non-specific effects between responders and non-26 responders related to daily contact with research staff (i.e. behavioural activation). 27 28 29

Physical Examination: A complete physical examination will be performed at the screen visit. The complete 30 physical examination will consist of an assessment of the following: general appearance, skin, oedema, 31 lymphadenopathy, head and neck, ears, nose, throat, abdomen, respiratory system, cardiovascular system, 32

neurological system and musculoskeletal system.

Laboratory Assessments: Laboratory measures will be obtained including heamatology, serum chemistry, 35

liver and kidney function, thyroid function, cholesterol lipid screen, plasma electrolytes (including calcium and 36 magnesium), quantitative beta Hcg levels (for all females of childbearing age), and serum levels for the mood 37 stabilizers lithium/valproate in patients taking those medications at the screen visit. 38 39

We propose to utilize the advanced technology to facilitate accurate targeting for this purpose. Participants will 41

undergo an MRI of the brain in order to accurately target the left DLPFC. Using a 3T Philips scanner we will 42 obtain brain scans. Patients will undergo a 90-minute MRI procedure consisting of a high-resolution T1 43

anatomical sequence for coil placement (10 min), a 48 min Single Voxel MRS sequence targeting both right and 44 left hippocampus as well as the right and left prefrontal cortex (approximately 12min for each scan), a 5 min T2 45 weighted and a 10 min T2* BOLD fMRI sequence during the resting state for assessment of whole-brain 46 functional connectivity.

All participants will complete the MRI procedure prior to the commencement of rTMS and post rTMS 49 treatment. All participants who completed a minimum of ≥15rTMS treatments will also complete MRI 50 procedures post rTMS treatments. 51 52

Participants will receive either daily iTBS-rTMS or sham-rTMS for four weeks (20 rTMS sessions) once daily 54 on weekdays. Prior to the first treatment, each subject's motor threshold (MT) will first be determined using an 55 established method of neuronavigated TMS over the primary motor cortex. At the first visit for rTMS, the study 56 team will construct a map of each individual's brain from the MRI to aim and target the stimulation work 57

properly. Next, a short stimulation procedure will be performed called motor threshold testing to determine the 58

proper strength of the rTMS, by observing the movements of the hand in response to the stimulation. The 59 rTMS team will locate the motor cortex based on the MRI map of the brain, and use single stimulation at a time 60

to try and make participant's right hand move. The whole procedure will be repeated until the technician has 61 determined which strength of stimulation is best for each participant. The whole motor threshold procedure 62 takes about 3 minutes.

Protocol-Version-8.1; Date 18 December 2018

The rTMS system being used for this study involves a method of delivering active-iTBS-rTMS and sham-65 rTMS in a manner in which blinding is preserved at all times during the study. All participants will have 66 electrodes placed on the scalp capable of delivering small currents to reproduce the sensation of iTBS-rTMS in 67

sham-rTMS in addition to a 'click'. The system has the capability of administering either active iTBS-rTMS or 68

sham-rTMS based on the patient ID and the blinding code which has been entered. 69 70 iTBS rTMS treatment : 71

Treatment consists of 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off; 600 pulses per session; total duration of 72 3 min 9 s. 120% rMT.

Sham rTMS treatment: Sham rTMS involves a click replicating the sound of the magnetic discharge, without 75 any magnetic pulse being delivered.

The Daily Evaluation Questionnaire will be administered before each rTMS session to ensure that the patient 78

can safely receive the treatment. The study doctor reserves the right to refuse treatment for that day if the patient 79

has recently consumed alcohol/street drugs, or is sleep deprived, or for any another factor that would 80 substantially increase the patients risk for seizure. 81

The Comfort Rating Questionnaire (CRQ) will also be administered daily to assess the participant's perception 82

and potential side effects during rTMS treatment (CRQ-A) and after treatment (CRQ-B). If the participant failed 83

to fill out the assessment at home, the CRQ-B will be filled out at UBC before the next day's treatment session. 84 85

The induction of electrical current in target brain regions aims to modulate its activity and connectivity to other 87 brain regions. This electrophysiological outcome can be measured using quantitative electroencephalography 88

(EEG), a safe non-invasive procedure involving recording of cortical electrical activity through electrodes 89 placed on the scalp. 90 91

Patients will undergo a simultaneous EEG-NIRS protocol. We plan to perform electroencephalographic and 92

blood-flow characterization of the effects of iTBS on the left DLPFC using 61 recording sites determined using 93

1-20 System of Electrode Placement, an electrode cap and sintered Ag-AgCl electrodes (1000 Hz A/D rate; 0.10 94

Hz high pass, 200 Hz low pass; gain = 10K; nose reference; impedances ≤ 10 kΩ), we will record resting state 95 EEG and NIRS. 96 97

Upon entering the laboratory, participants will be seated in a comfortable chair within a sound-attenuated room. 98

To make the EEG recordings, a mesh cap with small sensors embedded in it will be placed on the participant's 99 head, and a small sensor will be placed above and below their left eye. The skin beneath the sensors will be 00 cleaned, and a gel will be used to allow contact between the scalp and the sensor.

Functional near-infrared spectroscopy will be recorded by a NIRScout 32-32 device (NIRxMedizintechnik 03

GmbH, Berlin, Germany) with 24 LED sources (intensity 5mW/wavelength) and 32 detectors placed on the 04 frontal, temporal and parietal areas of the scalp. Within each area, two sources and three detectors will be 05 placed. The distance between a source and its neighboring detector will be 3 cm. Each source-detector pair at 3 06 cm distance will form a channel, resulting in five channels per area and 64 channels in total. The emitted light 07 from sources will be with wavelengths 760 and 850 nm, the sampling rate will be 6.25 Hz. 08 09

EEG will be recorded during three paradigms. The first is a resting EEG paradigm, in which participants will be 10 asked to sit quietly with their eyes closed for 5 minutes while their brainwaves are being recorded and then for 5 11 more minutes with their eyes open fixated on a target visual stimulus on a monitor. These data will allow us to 12

Protocol-Version-8.1; Date 18 December 2018 investigate the magnitude of resting brainwave activity within certain frequency ranges at rest (power), and the 13 relationship between different recording sites on the scalp within those frequency ranges (coherence). 14 15

The second paradigm is an auditory entrainment paradigm. During this task, participants will listen to a series of 16 clicks delivered over headphones at specific frequencies. These stimuli encourage the brain to synchronize its 17 firing, or entrain, to the sounds. Previous research has shown that entrainment is associated with NMDA-18 mediated inhibitory function, which sets the pace for network firing. Therefore, this paradigm is an ideal probe 19

of neural network integrity in a study of rTMS stimulation comparisons. Entrainment data will allow us to 20

investigate the magnitude of neural firing at the stimulated frequencies (power) and the consistency of 21 entrainment over time (inter-trial coherence). The third task is a resting state EEG while listening a guided 22 meditation audio recording for 8minutes.

Both EEG and fNIRS will be done for all subjects once prior to the commencement and once post rTMS 25 treatments. Participants who completed a minimum of ≥15rTMS treatments will be completing the EEG and 26

fNIRS post rTMS treatments 27 28

10.6 Neurocognitive testing 29

The International Society for Bipolar Disorders-Battery for Assessment of Neurocognition (ISBD-BANC) will 30 be administered to assess cognitive functioning prior to the first rTMS treatment and after the last rTMS Trail Making Test-part A (TMT-A), and Animal Naming Fluency Test from MCCB will be administered 38

to assess a patient's processing speed. 39 b) Attention: The Continuous Performance Test-Identical Pairs (CPT-IP) from MCCB will be administered 40

to assess a patient's attention. Spatial Span from MCCB will be administered to assess a patient's working memory. 43 d) Verbal Memory: The California Verbal Learning Test (CVLT-II) will be administered to assess a patient's 44 verbal memory. The standard form will be used prior to rTMS treatment and an alternate form will be used 45 at post rTMS treatment to minimize practice effects. 46 e) Nonverbal memory: The Brief Visuospatial Memory Test-Revised (BVMT) from MCCB will be 47 administered to assess a patient's nonverbal memory. 48 f) Executive Functioning: The Stroop Test and Trail Making Test-part B (TMT-B) will be administered to 49 assess a patient's executive functioning. 50 g) Premorbid IQ Test: North American Adult Reading Test will be administered to assess a patient's verbal 51 intellectual ability. 52 53

Commuting requirements for participants will represent the single greatest time commitment. Second to this, 55 clinical assessments will constitute the next most significant component, followed by the rTMS treatment itself. 56

The screening procedures will be spread over a week and will take 3-7 hours depending on the eligibility and 57 the procedures done. This is followed by 4 weeks of rTMS treatments and daily self-report questionnaires, 58

which is estimated to take approximately 15-30 minutes per session including the set up time, therefore a total 59

of 5-10hrs for the 4 weeks. The weekly clinical assessments and self-report questionnaires at baseline and 60 week-2 estimated to take 40. A second set of MRI, neurocognitive testing, EEG & fNIRS, including clinical 61 assessments post rTMS treatments will take 4.5-5hrs. 62 63

10.8Efficacy measures 64

The primary efficacy outcome is improvement in depressive symptoms as measured by MADRS scale score 65 from baseline to endpoint. Secondary outcomes are clinical response, clinical remission as well as quality of life 66 and neurocognitive function. 67 68 10.9 Withdrawal criteria 69 10.9.1 Reasons for withdrawal 70 a) Subjects meeting any of the following criteria will be withdrawn from the study: 71  Has a serious or intolerable Adverse Event (see section 11.2 on AEs and SAEs).

 Requires a change in current medication that is prohibited by the protocol.

 Does not follow guidelines specified in the protocol.

 Is non-adherent with study protocol (defined as missing 3 consecutive daily sessions of rTMS).

 Withdraws consent.

 Any signs of suicidal ideation during the clinical investigation (a score of 4 or more on iteam-10 77 of MADRS).

Subjects who become pregnant during rTMS treatment must immediately be withdrawn from the trial. A report 81 must be submitted to the IRB. Clinicians will follow local and clinical regulatory guidelines for monitoring and 82

documentation of such events. 83 84

If a subject prematurely withdraws from the study, the reason for withdrawal will be recorded in the CRF.

Subjects who withdraw from the study prematurely will be asked to undergo a clinical assessment. 87 88

The investigator reserves the right to discontinue the study at any time for any reason. Such a termination must 90 be implemented by the investigator, in a time frame that is compatible with the subject's well-being. notable. 30 The most common complaint pertains to tenderness at the site of stimulation and a headache after 00 treatment (28-39% vs 15% in sham-controlled trials). This is typically relieved by simple non-opioid analgesics. 01 02

There is a potential for hearing impairment due to the 'click' that is produced by rapid mechanical deformation 03 of the stimulating coil when current is discharged. The intensity of the noise is often underestimated due to its 04 brief nature, and can result in hearing damage. This, however, is prevented by the use of ear plugs. 05 06

Protocol-Version-8.1; Date 18 December 2018

In both depressed and healthy subjects, there is a small amount of literature on the possibility of inducing manic 07 and hypomanic symptoms. This small risk for inducing manic symptoms with rTMS is similar to that of 08 electroconvulsive therapy. Although this occurs in a small number of patients, it is a possibility which can be 09 partially anticipated in this study design by performing a thorough patient and family history suggestive of any 10 episodes of mania or hypomania. 11 12 11.1.2 Treatment Emergent Affective Switch 13

Treatment of bipolar depression can be associated with the development of mania/hypomania. Though the 14 available literature suggests that this is rare in bipolar disorder (approximately 1% in both active-rTMS and 15

sham-rTMS), it remains a concern. Patients will be carefully monitored and treatment discontinued should they 16 experience manic/hypomanic symptoms. 17 18

Intrinsic to rTMS is the risk of unintentionally triggering a seizure 30 . Though there have been no published 20

reports of seizure associated with rTMS in Bipolar Disorder, there have been reports in other populations. 21

Several risk factors have been identified, specifically a prior history of epilepsy or medication-induced seizures, 22

or other neurological condition, including prior cerebrovascular accident. In the absence of such predisposing 23

factors, dopaminergic medications have been associated with rTMS seizures, as have stimulation parameters 24

with inadequate inter-stimulation intervals (≤1 second) and stimulation parameters exceeding the motor 25 threshold (such as stimulation intensities as high as 208% of motor threshold).

For this reason, our protocol involves several attempts to reduce the risk of seizure. First, a careful medical 28

history is taken to evaluate past instances of seizure. Second, patients currently taking dopaminergic agents, 29

such as the antidepressant bupropion, will not be enrolled in this study.

A physician will be available on call during all rTMS sessions. Sessions will be filmed and maintained on a 32 temporary (automatically erased daily) USB drive in order to review any adverse event during stimulation. 33 34

12. ADVERSE EVENTS 35 36

All AEs, whether observed by the investigator, reported by the subject, noted from laboratory findings, or 37

identified by other means, will be recorded from the time the subject signs the ICF until the subject's final study 38

visit. All AEs will be recorded in the source documents. Causing no limitation of usual activities; the subject may experience slight discomfort.

Causing some limitation of usual activities; the subject may experience annoying discomfort.

Causing inability to carry out usual activities; the subject may experience intolerable discomfort or pain. 69

The investigator/ study physician will document his/her opinion of the relationship of the AE to treatment 71

using the criteria outlined in Table 3 . 72 73 Table 3 . Relationship of Adverse Events to Study procedure 74 75

A reaction that follows a reasonable temporal sequence from administration of the study procedure/drug; that follows a known or expected response pattern to the suspected procedure/drug; and that is confirmed by improvement on stopping or reducing number or treatment procedures/dosage of drug , and reappearance of the reaction on repeated exposure Probable A reaction that follows a reasonable temporal sequence from administration of the study procedure/drug; that follows a known or expected response pattern to the suspected procedure; that is confirmed by stopping or reducing study treatment procedure/ dosage of the drug; and that could not be reasonably explained by the known characteristics of the subject's clinical state.

A reaction that follows a reasonable temporal sequence from administration of the study procedure/drug; that follows a known or expected response pattern to the suspected procedure/drug; but that could readily be produced by a number of other factors.

A reaction that follows a reasonable temporal sequence from administration of the study procedure /drug; that follows a known or suspected response pattern to the suspected study procedure/drug; but that could reasonably be explained by known characteristics of the subject's clinical state.

Any event that does not meet the above criteria. Unblinding : Unblinding will happen immediately in the event of a seizure. The participant will immediately 27 be withdrawn from the study.

Trial Discontinuation: The trial will be discontinued if the treatment-emergent affective switches are increased 30

in the active rTMS group compared to the sham-rTMS group (α≤0.1) at the interim analyses planned after the 31 20 th participant. 32 33 34

13. STATISTICAL ANALYSES AND REPORTING 35 36

Reporting of results will occur in aggregate form with no personally identifiable data. 37 38

Primary hypotheses of change in MADRS scores will be tested using mixed effects model with repeated 40 measures while clinical response and remission will be determined using logistic regression. 41 42

 A sample size of 100 patients would allow 0.80 power to detect significance with a medium effect size 43 of ≥0.3 with an α≤0.05. 44 45

Statistical analyses will be carried out using SPSS v23 (Chicago, IL). Significance will be set at α≤.05. 47

Comparisons of dichotomous outcomes will use Chi-square tests (with 95% Confidence Interval). Baseline 48 comparisons of continuous variables will take place using Student's t-test for normally distributed data and 49

Mann-Whitney test for non-normally distributed variables.

The primary efficacy outcome is improvement in depressive symptoms as measured by MADRS scale score 52 from baseline to endpoint. Secondary outcomes are clinical response, clinical remission as well as quality of life 53 and neurocognitive function. 54

Analyses for MADRS change scores from baseline to week 4 will be performed using mixed effects model for 55

repeated measures with treatment group and treatment group-by-visit interaction as fixed effects and baseline 56 value and baseline-by-visit interaction as covariates. Response and remission rates will be determined using 57 logistic regression with the last observation carried forward. 58

Statistical analyses will be carried out using SPSS v23 (Chicago, IL). Significance will be set at α≤.05. 60

Repeated measures ANOVA will be employed, and secondary analyses will be performed using repeated 61 measures ANCOVA (controlling for HAMD-17 scores). 62 63

13.4 Neuroimaging 64

Statistical analyses will be carried out using SPSS v23 (Chicago, IL). Significance will be set at α≤.05. 65

Comparisons will be performed as a function of antidepressant response to rTMS using Student's t-test for 66

normally distributed data and Mann-Whitney test for non-normally distributed variables. Structural 67 morphometry will be analyzed using free surfer. Tractography, with stimulation site region of interest, will be 68 performed using Matlab. 69 70

In this double blind, randomized, placebo-controlled study, participants will be assigned a study ID that will be 72 a 4-digit code on all the CRF's with no relation to any personal identifiable information. These codes will be 73 linked to their identifiable information only in a locked filing cabinet accessible only to the principal 74 investigator or his designee.

In a separate locked filing cabinet accessible only to the blinding trustee (Ivan Torres, PhD, Associate 77

Professor, Mood disorders clinic) will be the master key linking the study ID to the treatment condition. The 78 data will only be unblinded at set interim analyses, at the conclusion of the trial or in the event of a seizure. 79 80

All data will be kept in anonymized format, on password protected computers and transferred only using 81 password protected encrypted USB drives. Data will be kept as required by ICH-GCP guidelines. 82 83 84

update. In: Informatics DoHSa

Psychosocial disability and work role function compared 89 across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders

Three times more days depressed than manic or hypomanic 92 in both bipolar I and bipolar II disorder

An estimate of the minimum economic burden of bipolar I and II disorders in the United 94 States

Absolute risk of suicide after first hospital contact in mental 96 disorder

Canadian Network for Mood and Anxiety Treatments 98 (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT 99 guidelines for the management of patients with bipolar disorder: update

Antidepressant 01 treatment in bipolar versus unipolar depression

Antidepressants for bipolar depression: 03 a systematic review of randomized, controlled trials

Antidepressants for the acute treatment of bipolar depression: a systematic 05 review and meta-analysis

The International Society for Bipolar Disorders (ISBD) 07 task force report on antidepressant use in bipolar disorders

The safety and efficacy of adjunctive modern 09 antidepressant therapy with a mood stabilizer or antipsychotic in acute bipolar depression: A meta-analysis of 10 randomized placebo-controlled trials. in review

Noninvasive techniques for probing neurocircuitry and treating illness: 12 vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current 13 stimulation (tDCS)

Response, remission and drop-out rates 15 following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a 16 systematic review and meta-analysis of randomized, double-blind and sham-controlled trials

Repetitive Transcranial Magnetic Stimulation (rTMS) for Treating Primary Major Depression: 20 A Meta-Analysis of Randomized, Double-Blind and Sham-Controlled Trials

A systematic review and meta-analysis on the efficacy 23 and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression

Efficacy of prefrontal theta-burst stimulation in refractory 26 depression: a randomized sham-controlled study

Nonpharmacotherapeutic Somatic Treatments for Bipolar Disorder 28 (ECT, DBS, rTMS)

H-coil repetitive transcranial magnetic 30 stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study

Protocol-Version-8.1; Date 18

Augmentative repetitive navigated transcranial magnetic 33 stimulation (rTMS) in drug-resistant bipolar depression

Transcranial magnetic stimulation in patients with 35 bipolar depression: a double blind, controlled study

Left prefrontal transcranial magnetic stimulation 37 (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy

What saccadic eye movements tell us about TMS-induced 40 neuromodulation of the DLPFC and mood changes: a pilot study in bipolar disorders

Stimulating research: a prospective, randomized, double-blind, 43 sham-controlled study of slow transcranial magnetic stimulation in depressed bipolar patients

The clinical efficacy and safety of repetitive transcranial 46 magnetic stimulation (rTMS) in bipolar depression: a systematic review and meta-analysis of patients with 47 bipolar disorder included in randomized, double-blind, and sham-controlled trials. World Psychiatry in press

A rating scale for depression

A rating scale for mania: reliability, validity and 51 sensitivity

The 16-Item Quick Inventory of Depressive Symptomatology 55 (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with 56 chronic major depression

Inflammatory monocyte gene expression: trait or state 58 marker in bipolar disorder?

A review of the safety of repetitive transcranial magnetic 60 stimulation as a clinical treatment for depression

Each AE will be listed as a separate entry on an AE CRF. Screen failure patients will have AE information 78 noted in the source documentation. The investigator will provide information on dates of onset and resolution, 79intensity, seriousness, action(s) taken, changes in study drug usage, relationship to study procedure or drug, and 80 outcome (if applicable). For randomized subjects, an AE that worsens in intensity will be recorded as a new AE 81 entry in the AE CRF. 82 8312.3 Post-study Follow-Up of Adverse Events 84All AEs, including physical examination findings, or isolated clinically significant laboratory findings must be 85 followed until the event resolves, the condition stabilizes, the event is otherwise explained, or the subject is lost 86to follow-up. If resolved, a resolution date should be documented on the CRF. The investigator is responsible 87for ensuring that follow-up includes any supplemental investigations as may be indicated to elucidate the nature 88and/or causality of the AE. This may include additional laboratory tests or investigations, or consultation with 89other health care professionals, as is practical. 90 91

All SAEs will be recorded from the time the subject has signed the ICF until 30 days after the last study 93dose/procedure or final study visit, whichever is longer in duration. 94 95

Any untoward medical occurrence which: 97 Results in death 98 Is life threatening. Life-threatening means that the subject was, in the view of the investigator, at 99immediate risk of death from the reaction as it occurred at the time of the event; it does not refer to 00 an event that hypothetically might have caused death if it were more severe.

 Requires inpatient hospitalization, or, in the opinion of the investigator, prolongation of existing 02 hospitalization. Hospitalization for elective treatment or a pre-existing condition that did not worsen 03 during the clinical investigation is not considered an AE. 04  Results in persistent or significant disability or incapacity 05 Is a congenital anomaly or birth defect 06 07

Subjects experiencing an SAE or an emergency situation will be examined by a physician as soon as possible. 09The physician in attendance will do whatever is medically needed for the safety and well-being of the subject. 10The subject will remain under observation as long as medically indicated. Appropriate laboratory studies will be 11 conducted until all parameters return to normal or are otherwise explained or stable. The subject will be 12 followed until the SAE resolves or until the subject is medically stabilized. The Principal Investigator or 13 designee will notify the IRB, if necessary immediately (within 24 hours and no later than 7 days) of the SAE 14 and the outcome of the SAE.

If within the time of informed consent until 30 days after the last study dose/procedure, an investigator becomes 17aware of an SAE, then the event must be documented and reported as described in Section 12.4.3. 18 19

Serious Adverse Events must be reported within 24 hours of first knowledge of the event by study personnel to 21 the principal investigator and an SAE Form should be completed. It is important that the investigator provide 22his or her assessment of relationship to study procedure at the time of the initial report. 23