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Evaluation of a Novel Therapeutic Repetitive Transcranial Magnetic Stimulation
Technique Optimized for Increased Accessibility in Major Depression
Jean-Philippe Miron 1,2,3,4,5,6,7,*, Helena Voetterl 1,8, Linsay Fox 1, Molly Hyde 1, Farrokh Mansouri
1,3, Sinjin Dees 9, Ryan Zhou 1, Jack Sheen 1,3, Arsalan Mir-Moghtadaei 1,3, Daniel M.
Blumberger 3,4,10, Zafiris J. Daskalakis 3,4,10, Fidel Vila-Rodriguez 11, Jonathan Downar 1,2,3,4
1 Krembil Research Institute, University Health Network, Toronto, ON, Canada;
2 Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada;
3 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
4 Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
5 Unité de Neuromodulation Psychiatrique (UNP), Département de Psychiatrie, Centre
Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada;
6, Montréal, QC, Canada;
7, Montréal, QC,
Canada;
8 Department of Cognitive Neuroscience, Maastricht University, Maastricht, Limburg,
Netherlands;
9 Faculty of Engineering, McMaster University, Hamilton, ON, Canada;
10 Temerty Centre for Therapeutic Brain Intervention at the Centre for Addiction and Mental
Health, Toronto, ON, Canada;
11 Non-Invasive Neurostimulation Therapies Laboratory, Department of Psychiatry, University of
British Columbia, Vancouver, BC, Canada.
* Corresponding author
ABSTRACT WORD COUNT: 244
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MANUSRIPT WORD COUNT: 3824
TABLES AND FIGURES: 9
ABSTRACT
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BACKGROUND
Repetitive transcranial magnetic stimulation (rTMS) is effective in major depressive
disorder (MDD). However, technical complexity and operational costs might have been barriers
for its wide use and implementation in some jurisdictions, thereby decreasing accessibility.
OBJECTIVE
Our main goal was to test the feasibility of a novel rTMS protocol optimized for
practicality, scalability and cost-effectiveness. We hypothesized that our novel rTMS protocol
would be simple to implement and well-tolerated, but less costly and allow for more treatment
capacity.
METHODS
Treatment was administered in an open-room setting, allowing a single technician to
attend to multiple patients. Large non-focal parabolic coils held by custom-built arms allowed
simple yet efficient and accurate placement. We employed a low-frequency (LF) 1 Hz
stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved
devices. MDD participants received an initial accelerated rTMS course (arTMS) of 6
sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to
decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used
to measure severity of depression.
RESULTS
Forty-eight (48) patients completed the arTMS course. No serious adverse events
occurred, and all patients reported manageable pain levels. Response and remission rates were
35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course.
CONCLUSION
If rTMS could be delivered for lower cost at higher volume, while preserving efficacy,
safety and tolerability, it could warrant further investigation of this treatment as a first-line
intervention in MDD.
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TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04376697
INTRODUCTION
Major depressive disorder (MDD) is a common and disabling illness. Up to 50% of
patients experience a chronic or recurrent course, and 30 to 40% develop treatment-resistant
depression [1]. Furthermore, although antidepressants offer high convenience and simplicity of
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administration, discontinuation rates approach 50% after 3 months of use due to concern over
side effects and non-response [2]. Alternative treatments are therefore needed.
Repetitive transcranial magnetic stimulation (rTMS) is recognized as an effective
intervention in MDD, with recent studies and meta-analyses reporting response and remission
rates of up to 50-55% and 30-35%, respectively [3]. rTMS has an advantageous side effect
profile, with lower discontinuation rates than medication (~5% vs ~25%) [3]. Unfortunately, its
widespread adoption is impeded by several obstacles that limit clinical accessibility.
The main issue concerns high acquisition and operation costs, with average cost per
remission estimated to be of up to $6,146 in the US [4]. This is partly a result of the equipment
needed to deliver high-frequency (HF) protocols, as well as the need for continuous 1:1
technician-patient supervision during treatment. Technical challenges stem from the complexity
of the treatment, such as the need for precise positioning of the widely used figure-of-eight
(Fo8) focal coils over the target region.
Another area that remains to be refined is treatment course optimization. The current
treatment paradigm forces patients to travel to a treatment center every day for 6 weeks in order
to receive a full 30 session course. This can be discouraging, especially for working individuals
and those who have families. Several studies have explored “accelerated” rTMS (arTMS),
whereby multiple stimulation sessions are delivered per day to shorten the overall treatment
course duration. Several large trials of arTMS have consistently reported similar or better
remission and response rates than conventional once-daily rTMS [5–16]. Furthermore, the total
cumulative number of sessions needed to achieve maximal effect is still debated. So far,
findings from large rTMS trials have suggested a plateau in clinical response at ~30 sessions,
on average [17]. This has recently been challenged by a secondary analysis [18] from the
THREE-D trial [19], demonstrating differences in patients’ response trajectories to rTMS.
Indeed, some participants were still showing signs of improvement at 30 sessions (not reaching
a plateau), suggesting that a treatment extension might be needed in some individuals.
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To address these issues, we developed a novel rTMS technique optimized for maximum
practicality, scalability and effectiveness, while minimizing costs. We employed a safe, well-
tolerated low-frequency (LF) 1 Hz stimulation protocol on the lowest cost FDA-approved
devices, delivered via large parabolic coils held by low-cost custom arms enabling simple yet
accurate placement, in an open-room setting enabling supervision of multiple simultaneous
sessions. We also tested the effects of 1 Hz arTMS followed by a tapering course of once-daily
treatment. These technical refinements are designed to enable the provider to accelerate,
increase and maintain treatment response beyond what ‘standard of care’ rTMS can achieve,
while achieving higher patient volumes at lower cost.
We hypothesized that our novel rTMS technique would be safe, well-tolerated and
effective, while allowing cost-saving opportunities and therefore increasing accessibility.
METHODS
Participants
We conducted a prospective, single-arm, open-label feasibility study. Participants were
recruited after referral to the Poul Hansen Family Centre for Depression neurostimulation
specialty clinic, located at the Toronto Western Hospital, an academic healthcare centre which
is part of the University Health Network (UHN) in Toronto, Canada.
Adult (18-85 years of age) outpatients were included for study participation if they 1) had
a Mini International Neuropsychiatric Interview (MINI) confirmed MDD diagnosis (single or
recurrent episode) and 2) maintained a stable medication regimen from 4 weeks before
treatment start to the end of the study. We did not require participants to have had a minimal
number of failed antidepressant treatment in their current depressive episode. Exclusion criteria
were: 1) history of substance dependence or abuse within the last 3 months; 2) concomitant
major unstable medical illness; 3) cardiac pacemaker or implanted medication pump; 4) active
suicidal intent; 5) diagnosis of any personality disorder as assessed by a study investigator to
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be primary and causing greater impairment than MDD; 6) diagnosis of any psychotic disorder;
7) any significant neurological disorder or insult (including, but not limited to: any condition likely
to be associated with increased intracranial pressure, space occupying brain lesion, any history
of seizure confirmed diagnostically by neurological assessment [except those therapeutically
induced by ECT], cerebral aneurysm, Parkinson’s disease, Huntington’s chorea, dementia,
stroke, neurologically confirmed diagnosis of traumatic brain injury, or multiple sclerosis); 8) if
participating in psychotherapy must have been in stable treatment for at least 3 months prior to
entry into the study (with no anticipation of change in the frequency of therapeutic sessions, or
the therapeutic focus over the duration of the study); 9) any clinically significant laboratory
abnormality in the opinion of the investigator; 10) a dose of more than lorazepam 2 mg daily (or
equivalent) currently (or in the last 4 weeks) or any dose of an anticonvulsant due to the
potential to limit rTMS efficacy and 11) any non-correctable clinically significant sensory
impairment. All participants provided informed consent and this study was approved by the
Research Ethics Board of the University Health Network.
Study design and procedure
Treatment was delivered in an open room setting, allowing up to 4 participants to receive
treatment simultaneously, with the help of one or two technicians (Fig. 1). This was facilitated by
an easy-to-use coil placement system, with the Anchored Articulating Arm (AAA) concept at its
core (Fig. 2). AAAs are made out of readily available camera tripod equipment and are
anchored at their base to the corner of the treatment chair. Coils are held securely by a clamp
locking it to the AAA, maintaining position until treatment has been completed, at which time
they can be easily repositioned out of the way.
rTMS was delivered through MagPro R20 stimulators equipped with parabolic MMC-140
coils (MagVenture, Farum, Denmark). We recently published a case series on the safety,
tolerability, and effectiveness of those coils in MDD [20]. The resting motor threshold (rMT) was
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determined according to standard clinical practice, with the additional need to use the coil’s
middle ring for stimulation, where the electromagnetic field strength is at its highest [20,21]. We
used a previously published 1 Hz rTMS protocol (60 s on and 30 s off, 6 trains, 8.5 min total
stimulation time, 360 pulses/sessions, 120% rMT) over the right dorsolateral prefrontal cortex
(DLPFC) with the coil centred on the F4 EEG location (right-flipped adjusted BeamF3) [20,22].
Treatment consisted of an arTMS course of 6 sessions/day (50 min inter-sessions
intervals) over 5 days (on weekdays), thus totalling 30 sessions. After a 1-week gap, arTMS
was followed by a tapering course of once-daily stimulation (minimum of 20, maximum of 25
sessions), 3-5 days per week, to decrease the odds of relapse. Baseline visits were conducted
the week prior to arTMS initiation and consisted of a clinical assessment by a trained research
staff, navigation cap fitting and motor threshold calibration. Participants were clinically
reassessed at 3 subsequent timepoints: post-acute visits were conducted during the one-week
gap following arTMS; post-tapering visits were conducted within 7 days of tapering termination;
1-month follow-up visits were conducted 1-month (± 7 days) after the last tapering session.
Participants who missed any sessions of the arTMS course were withdrawn. All participants
were encouraged to complete the tapering course. The study timeline is illustrated in Fig. 3.
At each clinical assessment, participants completed the self-rated Beck Depression
Inventory – II (BDI-II), and research staff administered the Hamilton Rating Scale for Depression
17-item (HRSD-17). On each treatment day, participants also completed the BDI-II and were
queried about any adverse events. Self-rated pain intensity of the rTMS procedure was also
recorded on a verbal analogue scale (VRS – from 1 [no pain] to 10 [intolerable pain]). We also
recorded the number of serious adverse events and reasons for treatment discontinuation when
such events occurred. To ensure tolerability, stimulation intensity was adaptively titrated upward
as quickly as possible to the target intensity of 120% RMT, without exceeding maximum
tolerable pain. We recorded the number of sessions required to reach 120% rMT.
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Outcomes
The primary outcome was the degree of improvement following the tapering course as
illustrated by response and remission rates on the BDI-II. Secondary outcomes included score
changes and percent improvement. The same outcomes are reported on the HRSD-17.
Response was defined as score reductions of ≥ 50% from baseline. Remission was defined as
a score of ≤ 12 [23] on the BDI-II and ≤ 7 on the HRSD-17 [24]. We also assessed the number
of participants maintaining remission and response from at various timepoints, as well as BDI-II
scores trajectory across the entire study. Regarding suicidality, we assessed the number of
participants showing remission (number of participants starting with a suicidality score greater
than zero at baseline and decreasing to zero at reassessment). Suicidality scores are assessed
by item #9 on the BDI-II and item #3 on the HRSD-17.
RESULTS
From March 18 to September 27, 2019, 57 participants with MDD were assessed for
eligibility, 7 of whom were ineligible or declined to participate. 50 participants were thus enrolled
and started the study. Of these, 2 discontinued treatment during arTMS because of lack of
perceived efficacy and were lost to follow-up. 48 participants moved on to the tapering course
and were thus included in the final analysis. Of these, 3 participants discontinued before having
completed at least 20 sessions of the tapering course because of the lack of perceived efficacy.
45 participants thus completed the entire study, and 35 followed up at 1 month (Fig. 4).
Table 1 provides the baseline characteristics of the study participants. Mean age was
41.8 ± 12.2, with 56.3% female participants. Mean age of depression onset was 23.8 ± 10.8
years old, with average length of current episode 51.7 ± 78.2 months. 70.8% of participants
were receiving psychopharmacotherapy during the trial, with 58.3% taking at least one
antidepressant during the study. All participants had tried antidepressant medication in the past,
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with a mean of 5.2 ± 3.6 lifetime trials. Average Antidepressant Treatment History Form (ATHF)
total score was 4.2 ± 4.3. Average number of trials on the ATHF in the current episode was 1.4
± 2.6, with 39/48 (81.3%) of participants having had at least one adequate antidepressant trial in
their current depressive episode.
Regarding the primary outcome, 35.4% and 27.1% of participants had achieved
response and remission on the BDI-II, respectively. Secondary outcomes are presented in
Table 2. On the BDI-II, 10 out 12 (83.3%) who were responders post-acute treatment
maintained response post-tapering, and 6 out of 7 (85.7%) participants who were in remission
post-acute treatment maintained remission post-tapering. On the HRSD-17, 10 out of 11
(90.9%) maintained response, and 3 out 3 (100.0%) maintained remission. BDI-II scores over
the duration of the study are presented in Fig. 5. Responders showed rapid improvement during
the accelerated course to meet criteria for clinical response, having achieved on average
response post-acutely, and continued to show slow but steady additional improvement up to the
end of the tapering course. Data regarding suicidality are shown in Table 3. No participants
reported active suicidal intent at any point during the study.
Safety and tolerability outcomes are presented in Table 4. No serious adverse events
(AE) were reported at any point of the study. One patient was withdrawn at session 51 since he
reported visual symptoms suggestive of possible retinal detachment but was assessed and
cleared by ophthalmology (subsequent diagnosis of migraine equivalent). Overall, 39.6% of
participants reported at least one occurrence of an AE at some point during treatment, the most
common one having been headache (22.9%). All AEs were reported exclusively during the
arTMS course, with the exception of the previously mentioned participant with visual symptoms
at session 51. Pain ratings went from 5.6 ± 2.0 on the first treatment, down to 1.9 ± 1.9 on the
last treatment. The average rMT was 34.6 ± 5.7% of maximum stimulator output, resulting in a
mean target stimulation intensity (120%) of 41.8 ± 6.8%. All participants were able to reach their
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target stimulation intensity, averaging 2.4 ± 3.0 sessions (1.2 ± 0.4 days) to do so, with 33/48
(68.8%) able to achieve it during their first session of treatment. Average total number of
sessions was 54.1 ± 2.9, and mean overall treatment length, including the week gap between
arTMS and tapering course, was 8.39 ± 0.93 weeks.
Regarding data collection quality, all participants were reassessed within the established
time frame post-acutely. For post-tapering reassessments, the established boundary was within
7 days of the last treatment, and 4/48 (8.3%) participants were reassessed beyond that
objective. Finally, for 1-month follow-up visits, the established boundary was ± 7 days 1-month
post- last tapering rTMS sessions, with 1/35 patient having been reassessed below that
boundary (1 day too early), and 8/35 having been reassessed beyond that boundary (most
delayed by 12 days).
DISCUSSION
We present preliminary data for a novel rTMS technique optimized for widespread use.
Currently, most guidelines recommend rTMS use solely in treatment-resistant depression
(TRD). Specifically, the Canadian Network for Mood and Anxiety Treatments (CANMAT)
recommends use in MDD participants who have failed to respond to at least 1 antidepressant
[3], a decision mirrored in other international guidelines [17,25]. However, access could
potentially be broadened if treatments could be delivered safely in more centres, at higher
volumes and lower costs, with a faster onset of response. Our study thus attempted to resolve
these issues by offering several technical refinements.
First, treatment was delivered in an open-room setting, allowing one or two
technicians to treat up to 4 participants in parallel, compared to the usual one-on-one approach.
Even though such a setting could bring about some concerns about technician fatigue and
negative patient feedback, this was not reported. We also did not observe any negative
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interactions between participants that could have jeopardized treatment outcome, and several
participants anecdotally gave positive feedback about the more flexible scheduling of treatment
sessions enabled by the open setting. Overall, this approach merits qualitative assessment with
standardized feedback questionnaires for both technicians and participants. If successful on a
larger scale, we believe that this approach may reduce staffing demands, increase clinic
capacity and flexibility, and improve cost and accessibility. Given the current COVID-19
pandemic, reduce staffing might be a potential advantage in order to observe physical
distancing measures, but it would need to be conjugated with stringent infection control
procedures.
One innovation that permitted such a treatment setting was the design and use of our
novel AAAs. Standard articulated arms can be more expensive, while offering a limited range of
motion. Our AAAs are made of widely available camera tripod equipment and have been both
functional and reliable, with no material malfunctions observed. Their durable yet bendable
extended branch allowed for the treatment technician to easily and accurately position the coil
without tedious joint adjustments. Their anchoring to the treatment chair also eliminated any
standalone equipment or cart, creating a more spacious, barrier-free clinic. The mechanical
advantage of the anchoring point gives the patient the flexibility to raise or lower the incline of
their treatment chair without placement adjustment, as the coil is now anchored to the shifting
point of reference, thereby maintaining the coils' targeted area of focus. This custom solution
decreased operational complexity, allowing for better patient care, ease of use for the
technician, and more efficient use of space and equipment. Similar coil positioning equipment
would be relatively straightforward for rTMS manufacturers to adopt in future.
The use of 1 Hz stimulation is another major component allowing for simplified rTMS
delivery. Firstly, 1 Hz rTMS is the medically safest stimulation pattern available, having even
shown anti-seizure properties in epileptic patients [26]. Further, there exists empirical evidence
that 1 Hz rTMS is better tolerated than HF protocols [27], and also shows similar efficacy [28–
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30]. With preliminary data potentially showing a higher safety and tolerability profile, LF 1 Hz
could be considered in the future as a first line rTMS protocol. Beyond these factors, the
greatest advantage of 1 Hz rTMS lies in the low cost of the equipment it requires. HF rTMS
require higher-cost stimulators, with expensive cooling systems. 1 Hz rTMS on the other hand
can be delivered on more simple stimulators with coils that do not require cooling. This setup is
more affordable than the ones required for HF, with the possibility of additional cost reductions
in the future through higher volume use.
Parabolic coils also allow simplification of rTMS delivery. We previously published a
case report on their use [20], delineating their potential advantage over Fo8 coils. Indeed, large
parabolic coils may require less precise placement given their large electromagnetic field
compared to the target brain region – a factor also present with larger helmet-shaped coils [31].
Also, their central opening allows direct visualization of underlying landmarks, resulting in easier
accurate placement over the marked target. We also hypothesized that, given their possibly
weaker stimulation of the DLPFC owed to the aforementioned opening, parabolic coils may
function by stimulating adjacent neural substrates, such as the orbitofrontal cortex (OFC). Our
group also previously published a case series on 1 Hz OFC, which is theorized to be involved in
depression [32–34].
Another novel aspect of our study was the piloting of accelerated 1 Hz rTMS. We are
aware of only one small (n = 7) negative trial with limited stimulation course and duration (18
sessions over 10 days) [35]. Our results are encouraging, but overall limited response and
remission rates after the arTMS course would suggest that increasing the number of sessions
per day and the number of pulses delivered at each session may be necessary [5]. Indeed, a
recent arTMS pilot (n = 6) with highly refractory MDD patients using intermittent theta-burst
stimulation (iTBS), 1800 pulses/session, 10 sessions per day over 5 days, reported remission
rates of 66% [14]. A larger follow-up study (n = 21) in a less refractory MDD population reported
remission rates of up to 90% [36]. The rapid improvement in responders post-acutely (Fig. 5) is
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encouraging, showing that it is indeed possible to rapidly accelerate response to 1 Hz
stimulation in some individuals. This could justify the further study of this rTMS technique in
more severe inpatient cases, where suicidality is of concern and rapid response is at a
premium. Overall, final outcomes post-taper compared favorably to another large trial [19], as
well as a landmark meta-analysis [37], which may be explained by the high number of total
sessions. Supporting this observation, a recent study that offered up to 21 weeks of rTMS
reported remission rates of 72% [38]. Since there is a lack of data about 1 Hz arTMS alone
without the subsequent tapering period, we are unable to determine the impact or the necessity
of such an extension. It may well be possible that 1 Hz arTMS has a delayed effect, where
participants would have kept on improving without the extension course, as suggested in other
arTMS protocols [12]. Conversely, high relapse rates following arTMS are also of concern
[14,39].
We also included data regarding suicidality scores for each scale since arTMS has also
been studied in the treatment of acute suicidality [6,8]. In the future, suicidal ideation should be
assessed with either the Beck Scale of Suicide ideation (BSI) or the Columbia-Suicide Severity
Rating Scale (C-SSRS).
This preliminary study has several limitations. Of primary concern is the open-label
design and the absence of a sham control arm. It is to be expected that the various estimates of
effectiveness might be higher than what would be obtained in a randomized, sham-controlled
trial, which would represent the next logical step. In addition, the naturalistic approach of the
study does not allow estimates of efficacy, but only effectiveness. The design of the study, with
multiple reassessments throughout, presented logistical challenges, mainly with patient
adherence. Indeed, several participants did not adhere to the planned schedule, and were thus
reassessed outside of the planned boundaries. Additionally, we did not qualitatively assess our
open-room setting, as discussed previously. We also had 10 participants lost to follow-up at 1-
month, limiting interpretation of results at that timepoint. In future studies, this would need to be
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corrected to achieve more standardized measures. Furthermore, frequency of tapering course
varied between individuals. Although we recommended daily sessions for participants (5
sessions/week), a minimum of 3 sessions/week was tolerated, given the fact that this approach
has proven effective on its own [40]. Moreover, results did vary between the self-rated BDI-II
and the clinician-rated HRSD-17. Indeed, remission and response rates were higher post-
acutely and lower post-tapering and at 1-month follow-up visits on the BDI-II compared to
HRSD-17. Discrepancies between self- and clinician-rated scales are not unique to our studies
and have often been reported in MDD [41], showing the general limitation of mood scales, and
the need for objective biomarkers in psychiatry [42]. As a further matter, the weaker central field
in the parabolic coils used may have under-stimulated the DLPFC [20]; this may be correctable
in future by moving the central opening to an intermediate mark between F4, Fz and Cz. Due to
their less widespread use in clinical settings, results with 1 Hz rTMS on parabolic coils may not
generalize to more commonly used Fo8 coils. The 1 Hz protocol used, although highly tolerable
for participants, may also have been less effective due to its limited amount of pulses per
session. Given that increased number of pulses has been associated with increased response
in 1 Hz rTMS in some studies [43], it may be advantageous to increase the number of pulses
within the same time frame (e.g., 600 pulses in 10 min). Finally, although we did not require
participants to meet the usual requirement of TRD in our trial, the majority (>80%) of
participants had failed at least one adequate trial. We also did not have a minimal cut-off
regarding depression severity on the mood scales for study inclusion, but average baseline
scores on the BDI-II was in the severe range. Average HRSD-17 score was also higher than in
a recent large trial from our group [19].
Given its established efficacy in MDD and its lower side-effect profile compared to
medication, efforts should be made to make rTMS more accessible to the general public. The
current trend depicts increased costs and complexity associated with rTMS administration
[14,36]. However, the techniques demonstrated here may be suitable for safe use in a wider
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range of settings, and potentially could be adapted in future to enable home use of 1 Hz rTMS.
Besides eliminating the need for in-clinic visits, particularly relevant during the current COVID-
19 pandemic [44], home-based rTMS could potentially be delivered for as little as $10/day,
comparable to some medication regimens. Thus, if the presently described technique does
indeed achieve efficacy while preserving superior safety and tolerability, rTMS may serve as a
viable first-line treatment technique for treatment-naïve MDD patients or a home-based
maintenance technique for rTMS responsive patients.
CONFLICTS OF INTEREST
The authors declare no financial interests relative to this work. JPM reports research grants
from the Brain & Behavior Research Foundation NARSAD Young Investigator Award and salary
support for his graduate studies from the Branch Out Neurological Foundation. HV, LF, MH, FM,
SD, RZ, JS and AMM do not report any conflict of interest. DMB receives research support from
CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the
Campbell Family Research Institute. He received research support and in-kind equipment
support for an investigator-initiated study from Brainsway Ltd. He is the site principal
investigator for three sponsor-initiated studies for Brainsway Ltd. He also receives in-kind
equipment support from Magventure for investigator-initiated research. He received medication
supplies for an investigator-initiated trial from Indivior. ZJD has received research and
equipment in-kind support for an investigator-initiated study through Brainsway Inc and
Magventure Inc. His work was supported by the Ontario Mental Health Foundation (OMHF), the
Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH)
and the Temerty Family and Grant Family and through the Centre for Addiction and Mental
Health (CAMH) Foundation and the Campbell Institute. FVR receives research support from
CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal
Health Research Institute, and in-kind equipment support for this investigator-initiated trial from
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 17, 2020. .https://doi.org/10.1101/2020.06.15.20132092doi: medRxiv preprint
MagVenture. He has received honoraria for participation in advisory board for Janssen. JD
reports research grants from CIHR, the National Institute of Mental Health, Brain Canada, the
Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Weston
Foundation, the Klarman Family Foundation, the Arrell Family Foundation, and the Buchan
Family Foundation, travel stipends from Lundbeck and ANT Neuro, in-kind equipment support
for investigator-initiated trials from MagVenture, and is an advisor for BrainCheck, TMS Neuro
Solutions, and Restorative Brain Clinics.
ACKNOWLEDGEMENT
JPM would like to thank the Brain & Behavior Research Foundation and the Branch Out
Neurological Foundation for their financial support of this project. We would like to thank Terri
Cairo, Julian Kwok, Meaghan Todd, Nuno Ferreira, Thomas Russell and Eileen Lam for
their involvement and organizational support throughout this project.
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Age, years 41.8 (12.2)
Women 56.3%
Education, years 17.1 (3.2)
Left-handed 6.3%
Age of onset, years 23.8 (10.8)
Length of current depressive episode, months 51.7 (78.2)
Comorbid anxiety 81.3%
Currently working 64.6%
Baseline BDI-II 35.0 (9.8)
Baseline HRSD-17 23.8 (5.3)
Receiving psychopharmacotherapy during treatment 70.8%
Antidepressant 58.3%
Antidepressant combination 22.9%
Antipsychotic augmentation 14.6%
Lithium augmentation 4.2%
Psychostimulant augmentation 14.6%
T3 augmentation 2.1%
Benzodiazepine 18.8%
Number of past antidepressant trials, lifetime 5.2 (3.6)
ATHF total score 4.2 (4.3)
ATHF number of trials, current episode 1.4 (1.1)
ATHF highest score 2.6 (1.6)
Data are mean (SD) or number of participants (% of total). BDI-II
= Beck Depression Inventory-II, HRSD-17 = 17-item Hamilton
Rating Scale for Depression, ATHF = Antidepressant Treatment
History Form.
Table 1: Baseline demographic and clinical characteristics (n =
48)
BDI-II
Response post-acute 12/48 (25.0%)
Response post-taper 17/48 (35.4%)
Response 1-month 10/35 (28.6%)
Remission post-acute 8/48 (16.7%)
Remission post-taper 13/48 (27.1%)
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BDI-II
Remission 1-month 8/35 (22.9%)
Score baseline 35.0 (9.8)
Score change post-acute 25.8 (12.2)
Score change post-taper 22.2 (13.1)
Score change 1-month 21.5 (12.1)
Percent improvement post-acute 27.4% (27.8%)
Percent improvement post-taper 37.9% (33.0%)
Percent improvement 1-month 36.1% (34.7%)
HRSD-17
Response post-acute 11/48 (22.9%)
Response post-taper 28/48 (58.3%)
Response 1-month 21/35 (60.0%)
Remission post-acute 3/48 (6.3%)
Remission post-taper 18/48 (37.5%)
Remission 1-month 13/35 (37.1%)
Score baseline 23.8 (5.3)
Score change post-acute 16.3 (6.6)
Score change post-taper 12.2 (8.0)
Score change 1-month 11.3 (7.4)
Percent improvement post-acute 31.4% (23.8%)
Percent improvement post-taper 48.6% (31.9%)
Percent improvement 1-month 52.4% (28.5%)
Data are mean (SD). For remission and response rates, data are n (% of
participants assessed). BDI-II = Beck Depression Inventory-II, HRSD-17 = 17-
item Hamilton Rating Scale for Depression.
Table 2: Response and remission rates, changes in depression severity scores
and percent improvement throughout the study
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Remission post-acute 12/31 (38.7%)
Remission post-taper 15/31 (48.4%)
Remission 1-month 13/23 (56.5%)
HRSD-17
Remission post-acute 16/38 (42.1%)
Remission post-taper 20/38 (52.6%)
Remission 1-month 17/28 (60.7%)
Data are n (% of participants assessed). Suicidality item is #9
on the BDI-II and #3 on the HRSD-17. BDI-II = Beck
Depression Inventory-II, HRSD-17 = 17-item Hamilton Rating
Scale for Depression.
Table 3: Remission rates regarding suicidality
Serious AE 0/48 (0.0%)
AE total 19/48 (39.6%)
Headache 11/48 (22.9%)
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Fatigue 7/48 (14.6%)
Nausea 2/48 (4.2%)
Scalp tenderness 3/48 (4.2%)
Hand twitching 1/48 (2.1%)
Insomnia 3/48 (6.3%)
Dizziness 1/48 (2.1%)
Anxiety 3/48 (6.3%)
Jaw pain 1/48 (2.1%)
Visual symptoms 1/48 (2.1%)
First treatment pain VRS 5.6 (2.0)
Last treatment pain VRS 1.9 (1.9)
Number of days to reach target stimulation intensity 3.8 (6.3)
Number of participants (n=48) reporting adverse events (AE - %). For
pain, data mean (SD). VRS = Verbal Rating Scale.
Table 4: Adverse events
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Figure 1: Clinical setup - 4 recliners equipped with AAAs holding rTMS coils, connected to the
rTMS stimulators. Treatment was delivered in an open room setting, allowing up to 4 participants to
receive treatment simultaneously, with the help of one or two technicians. AAA = Anchored
Articulating Arm
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Figure 2: Anchored Articulating Arm (AAA) schematic - AAAs are made out of inexpensive camera
tripod equipment and are anchored at their base to the corner of the treatment chair. Coils are held
securely by a clamp locking it to the AAA, maintaining position until treatment has been completed,
at which time they can be quickly twisted out of the way.
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Figure 3: Study timeline - Treatment consisted of an arTMS course of 6 sessions/day (50 min inter-
sessions intervals) over 5 days (on weekdays
totalling 30 sessions. After a 1-week gap, arTMS was followed by a tapering course of once-daily stimulation (minimum of 20, maximum
of 25 se
days per week, to decrease the odds of relapse. Baseline visits were conducted the week prior to arTMS initiation and consist
ed of a clinical asse
a trained research staff, navigation cap fitting and motor threshold calibration. Patients were clinically reassessed at 3 subsequent timepoints:
po
visits were conducted during the one-week gap following arTMS; post-taper visits were conducted within 7 days of tapering termination; 1-
month
visits were conducted 1-month (± 7 days) after the last tapering session. arTMS = accelerated repetitive transcranial magnetic stimulation,
ATHF
Antidepressant Treatment History Form, MINI = Mini International Neuropsychiatric Interview, BDI-II = Beck Depression Inventory-II, HRSD-
17 =
Hamilton Rating Scale for Depression
ys), thus
sessions), 3
-5
ssessment by
post
-acute
th follow
-up
F = Average
= 17
-item
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57 patients assessed for eligibility
7 excluded
2 did not meet inclusion criteria
5 declined to participate
50 patients enrolled
2 patients discontinued treatment
during the arTMS course because of
lack of perceived efficacy and were lost
to follow-up
48 patients went on the tapering
course and were included in the
analysis
3 patients discontinued treatment
before having completed 50 sessions
because of lack of perceived efficacy
45 patients completed the trial
(50+ sessions)
35 patients followed up at 1-month
Figure 4: Trial CONSORT flow diagram - arTMS = accelerated repetitive
transcranial magnetic stimulation.
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Fig. 5.
Trajectories of improvement on the BDI-II. Responders showed rapid improvement during the accelerated course, having achieved
res
on average response post-acutely, and continued to show slow but steady additional improvement up to the end of the tapering course.
Use o
background shading delineates arTMS from tapering course. BDI-II = the Beck Depression Inventory – II, arTMS = accel
erated repetitive trans
magnetic stimulation, Tx = treatment (rTMS session)
response
e of
nscranial
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