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Journal of Aective Disorders Reports 4 (2021) 100077
Contents lists available at ScienceDirect
Journal of Aective Disorders Reports
journal homepage: www.elsevier.com/locate/jadr
Research Paper
Evaluation of a 5 day accelerated 1 Hz repetitive transcranial magnetic
stimulation protocol in major depression: A feasibility study
Jean-Philippe Miron
a , b , c , d , ∗
, Molly Hyde
a , 1
, Linsay Fox
a , 1
, Jack Sheen
a , b
, Helena Voetterl
a , e
,
Farrokh Mansouri
a , b
, Véronique Desbeaumes Jodoin
d
, Ryan Zhou
a
, Sinjin Dees
f
,
Arsalan Mir-Moghtadaei
a , b
, Daniel M. Blumberger
b , c , g
, Zaris J. Daskalakis
b , c , g , h
,
Fidel Vila-Rodriguez
i
, Jonathan Downar
a , b , c
a
Krembil Research Institute, University Health Network, Toronto, ON, Canada
b
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
c
Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
d
Centre Hospitalier de l’Université de Montréal (CHUM) et Centre de Recherche du CHUM (CRCHUM), Département de Psychiatrie, Faculté de Médecine, Université de
Montréal, Montréal, QC, Canada
e
Department of Cognitive Neuroscience, Maastricht University, Maastricht, Limburg, the Netherlands
f
Faculty of Engineering, McMaster University, Hamilton, ON, Canada
g
Temerty Centre for Therapeutic Brain Intervention at the Centre for Addiction and Mental Health, Toronto, ON, Canada
h
Department of Psychiatry, University of California San Diego, San Diego, CA, USA
i
Non-Invasive Neurostimulation Therapies Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
Keywords:
arTMS
TMS
rTMS
low-frequency
LF
Background: Repetitive transcranial magnetic stimulation (rTMS) is an eective intervention in major depressive
disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retain-
ing similar eectiveness would thus increase the practicality and scalability of the technique, and therefore its
accessibility.
Objective: We assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this
novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course.
Methods: We conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a
one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session,
50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a gure-of-eight
coil at 120% of the resting motor threshold (rMT). Primary outcomes were response and remission rates on the
Beck Depression Inventory-II (BDI-II).
Results: Response and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased
to 43.3% and 30.0% at follow-up 4 weeks after treatment. No serious adverse events occurred. All participants
reported manageable pain levels.
Conclusion: 1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Validation in a randomized
trial will be required.
Trial registration: ClinicalTrials.gov Identier: NCT04376697.
1. Introduction
Major depressive disorder (MDD) is now the leading cause of
disability worldwide, with lifetime suicide rates as high as 15%
∗ Corresponding author at: Centre Hospitalier de l’Université de Montréal (CHUM) et Centre de Recherche du CHUM (CRCHUM), Département de Psychiatrie,
Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
E-mail address: jean-philippe.miron@umontreal.ca (J.-P. Miron).
1 Equal authorship.
(
Friedrich, 2017 ; Lam et al., 2016 ). Even though antidepressant med-
ication oers convenience and simplicity of administration, discontinu-
ation rates are close to 50% at 3 months, resulting from side-eects and
lack of clinical response ( Kennedy et al., 2016 ).
https://doi.org/10.1016/j.jadr.2021.100077
Received 27 December 2020; Received in revised form 1 January 2021; Accepted 11 January 2021
Available online 12 January 2021
2666-9153/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
J.-P. Miron, M. Hyde, L. Fox et al. Journal of Affective Disorders Reports 4 (2021) 100077
Repetitive transcranial magnetic stimulation (rTMS) is well estab-
lished as an eective intervention in MDD, with an advantageous side-
eect prole over medication ( Brunoni et al., 2017 ; Lefaucheur et al.,
2020 ; Milev et al., 2016 ). Recent meta-analyses report response and re-
mission rates of up to 50–55% and 30–35%, respectively ( Milev et al.,
2016 ). Unfortunately, standard rTMS involves treatment courses over
several weeks. This complicates treatment logistics for many patients
who cannot take time away to attend daily clinic visits for this period
of time.
To address this, accelerated rTMS (arTMS), where treatment is de-
livered multiple times daily, has been studied for over a decade. arTMS
has been the subject of several open-label studies ( Cole et al., 2020 ;
Dardenne et al., 2018 ; Fitzgerald et al., 2019a ; Holtzheimer et al.,
2010 ; Jodoin et al., 2019 ; McGirr et al., 2015 ; Modirrousta et al.,
2018 ; Schulze et al., 2017 ; Tor et al., 2016 ; Williams et al., 2018 ), ran-
domized controlled trials (RCTs) ( Baeken, 2018 ; Baeken et al., 2013 ;
Desmyter et al., 2016 ; Duprat et al., 2016 ; Fitzgerald et al., 2018 ;
George et al., 2014 ; LOO et al., 2007 ; Theleritis et al., 2017 ), as well as
meta-analyses ( Chen et al., 2020 ; Sonmez et al., 2019 ). Some evidence
suggests that this approach allows comparable eectiveness to standard
once-daily rTMS, while shortening treatment length ( Fitzgerald et al.,
2018 ). Recently, high-dosage highly-accelerated and personalized in-
termittent theta-burst (iTBS) arTMS feasibility studies have reported re-
mission rates of up to ~90%, while delivering treatment over only 5
days ( Cole et al., 2020 ; Williams et al., 2018 ).
However, arTMS has not been well studied for 1 Hz protocols
( Miron et al., 2020a , 2020b ). On conventional once-daily regimens, 1 Hz
has shown superiority over sham, with some studies also suggesting sim-
ilar ecacy to high-frequency (HF) ( Berlim et al., 2012 ; Brunoni et al.,
2017 ; Lefaucheur et al., 2020 ; Milev et al., 2016 ; Miron et al., 2020a ).
1 Hz also oers several potential advantages over HF, including less
seizure risks ( Sun et al., 2012 ; Vila-Rodriguez et al., 2015 ), better tol-
erability ( Kaur et al., 2019 ), and the potential for implementation on
simpler, lower-cost equipment ( Miron et al., 2020b , 2020a ), thus possi-
bly increasing scalability and accessibility.
To address the aforementioned issues, we developed an accelerated
low-frequency protocol applying 1 Hz stimulation sessions 8 times daily
for 5 days. We hypothesized that the novel protocol would be safe, well-
tolerated, and eective, while reducing course length and accelerating
clinical improvement.
2. Methods
2.1. Participants
We conducted a prospective, single-center, single-arm, open-label
feasibility study. Participants were treated at the Krembil Research In-
stitute, located at the Toronto Western Hospital, an academic health-
care center which is part of the University Health Network (UHN) in
Toronto, Canada. Adult (18–85 years of age) rTMS-naïve outpatients
were included for study participation if they 1) had a Mini International
Neuropsychiatric Interview (MINI) conrmed 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. Exclusion crite-
ria were: 1) history of substance dependence or abuse within the last 3
months; 2) concomitant major unstable medical illness; 3) cardiac pace-
maker or implanted medication pump; 4) active suicidal intent; 5) di-
agnosis of any personality disorder as assessed by a study investigator
to be primary and causing greater impairment than MDD; 6) diagnosis
of any psychotic disorder; 7) any signicant neurological disorder or
insult (including, but not limited to: any condition likely to be associ-
ated with increased intracranial pressure, space occupying brain lesion,
any history of seizure conrmed diagnostically by neurological assess-
ment [except those therapeutically induced by ECT], cerebral aneurysm,
Parkinson’s disease, Huntington’s chorea, dementia, stroke, neurologi-
cally conrmed diagnosis of traumatic brain injury, or multiple scle-
rosis); 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 sig-
nicant 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 poten-
tial to limit rTMS ecacy; 11) any non-correctable clinically signicant
sensory impairment and 12) any signicant cardiovascular or metabolic
disorder or insult including, but not limited to: coronary artery disease,
abnormal heart rhythms, heart failure, cardiac valve disease, congeni-
tal heart disease, cardiomyopathy, vascular disease, dyslipidemia, dia-
betes, or hypertension (this last criteria was added because participants
were also enrolled in a cardiac biomarker study, which results will be
published elsewhere). All participants provided informed consent and
this study was approved by the Research Ethics Board of the University
Health Network.
2.2. Study design and procedures
rTMS was delivered through a MagPro R20 stimulator equipped
with a MC-B70 coil (MagVenture, Farum, Denmark). Resting motor
threshold (rMT) was determined according to standard techniques
( McClintock et al., 2017 ). Treatment consisted of an arTMS course of 8
hourly sessions per day over 5 consecutive weekdays (Monday through
Friday), thus totaling 40 sessions in ve days. Each rTMS session con-
sisted of low-frequency (LF) 1 Hz stimulation delivered over a 10 min
period (1 single train, 600 pulses per session, 50-minute intersession
interval) at 120% of rMT over the right dorsolateral prefrontal cortex
(R-DLPFC), localized according to a previously published heuristic ap-
proximating the F4 EEG site ( Mir-Moghtadaei et al., 2017 ).
Baseline assessments were completed during the week prior to arTMS
initiation and consisted of a clinical assessment by trained research
sta, including completion of the self-rated Beck Depression Inventory-
II (BDI-II) and clinician-rated Hamilton Rating Scale for Depression 17-
item (HRSD-17), cap tting, and motor threshold calibration. Partici-
pants were reassessed 1 week and 4 weeks after treatment on the BDI-II
and HRSD-17. Participants were asked not to change their medication
regimen throughout the whole treatment, up until the 1-week reassess-
ment. Participants who missed any one of the treatment days or 4 or
more sessions overall were withdrawn.
To study response trajectory during treatment days, participants also
completed the BDI-II at the beginning of each treatment day before rTMS
initiation, where they were queried about any adverse events. Partici-
pants also completed the BDI-II immediately following their nal rTMS
session after the last treatment day. Self-rated pain intensity of the rTMS
procedure was recorded on a verbal analog scale (VRS –from 0 [no pain]
to 10 [intolerable pain]). Moreover, serious adverse events and reasons
for treatment discontinuation were recorded when such events occurred.
Stimulation intensity was adaptively titrated upward, aiming to reach
the target intensity of 120% rMT on the rst session of treatment, with-
out exceeding maximum tolerable pain. We recorded the number of ses-
sions required to reach 120% rMT.
2.3. Outcomes
Primary outcome measures were response and remission rates on
the BDI-II. Secondary outcomes included score changes and percent im-
provement. These outcomes were also calculated on the HRSD-17. Re-
sponse was dened as score reductions of ≥ 50% from baseline. Remis-
sion was dened as a score of ≤ 12 ( Riedel et al., 2010 ) on the BDI-II
and ≤ 7 on the HRSD-17 ( Zimmerman et al., 2004 ). We also analyzed
the outcome trajectories using the BDI-II.
2
J.-P. Miron, M. Hyde, L. Fox et al. Journal of Affective Disorders Reports 4 (2021) 100077
Fig. 1. Trial CONSORT ow diagram.
2.4. Statistical analysis
Descriptive statistics were performed on baseline characteristics
(age, sex, comorbid anxiety, age of onset of MDD, duration of current
MDD episode, total lifetime number of antidepressant medication trials,
total ATHF score and baseline BDI score) utilizing independent samples
t-tests (two-tailed) for continuous variables, and Chi-square tests for cat-
egorical variables. We also performed repeated measures analyses of
variance (ANOVA) on BDI-II score at dierent timepoints to assess the
eect of the treatment through time. Planned repeated contrasts were
used to make comparisons between the dierent evaluation times.
3. Results
From September 23, 2019 to February 13, 2020, 37 participants with
MDD were screened for eligibility, 4 of whom were deemed ineligible or
declined to participate; thus, 33 participants were enrolled and began
treatment. Of these, 3 discontinued during treatment and were excluded
from analysis: 2 participants lost interest and 1 participant was removed
by the attending physician after reporting visual symptoms suggestive of
possible retinal detachment on day 3 (subsequent diagnosis of migraine
equivalent). Thus, 30 participants completed the entire study ( Fig. 1 ).
Table 1 provides the baseline characteristics. Mean age was
43.5 ± 13.9, with 43.3% (13/30) female participants. Mean age of de-
pression onset was 21.4 ± 9.9 years old, with the average length of
current episode 13.0 ± 12.7 months. 83.3% of patients were receiving
psychopharmacotherapy during the trial, with 60.0% being on at least
one antidepressant during the study. Average Antidepressant Treatment
History Form (ATHF) total score was 6.6 ± 5.0. The average number of
trials on the ATHF in the current episode was 1.3 ± 1.2, with 24/30
(80.0%) having had at least one adequate antidepressant trial in their
current depressive episode.
Safety and tolerability outcomes are presented in Table 2 . No serious
adverse events (AE) were reported. Overall, 53.3% of patients reported
Table 1
Baseline characteristics ( n = 30).
Age, years 43.5 (13.9)
Wome n 43.3%
Education, year s 17.1 (3.8)
Left-handed 3.3%
Age of onset, years 21.4 (9.9)
Length of current depressive episode, months 13.0 (12.7)
Comorbid anxiety 70.0%
Baseline BDI-II 35.2 (9.2)
Baseline HRSD-17 19.8 (4.5)
Receiving psychopharmacotherapy during treatment 83.3%
Antidepressant 60.0%
Antidepressant combination 10.0%
Antipsychotic augmentation 16.7%
Psychostimulant augmentation 30.0%
Benzodiazepine 16.7%
ATHF total score 6.6 (5.0)
ATHF number of trials, current episode 1.3 (1.2)
ATHF highest score 3.3 (1.4)
Data are mean (SD) or number of participants (% of total). BDI-
II = Beck Depression Inventory-II, HRSD-17 = 17-item Hamilton Rat-
ing Scale for Depression, ATHF = Antidepressant Treatment History
Form.
Table 2
Adverse events.
Serious AE 0/30 (0.0%)
AE total 16/30 (53.3%)
Headache 10/30 (33.3%)
Fatig ue 6/30 (20.0%)
Nausea 8/30 (26.7%)
Insomnia 8/30 (26.7%)
Dizziness 5/30 (16.7%)
Jaw pain 2/30 (6.7%)
First treatment pain VRS 3.5 (2.0)
Last treatment pain VRS 1.7 (1.6)
Number of participants ( n = 48) reporting ad-
verse events (AE -%). For pain, data mean
(SD). VRS = Verbal Rating Scale.
at least one occurrence of an AE at some point during treatment, the
most commonly experienced being headache (33.3%). Pain ratings de-
creased from 3.5 ± 2.0 (rst treatment) to 1.7 ± 1.6 (last treatment).
Average rMT was 34.6 ± 7.0% of maximum stimulator output, result-
ing in a mean target stimulation intensity (120%) of 41.6 ± 8.5%. All
patients were able to reach their target stimulation intensity, averaging
1.1 ± 0.5 sessions to do so.
Table 3 presents outcomes of interest. Regarding the primary out-
come, response rate was 33.3% (10/30) at 1 week, which increased
to 43.3% (13/30) at 4 weeks. Similarly, remission rate increased from
13.3% (4/30) at 1 week to 30.0% (9/30) at 4 weeks. Scores decreased
from 35.2 (SD 9.2) at baseline down to 24.0 (11.7) at 1 week, and 23.5
(13.3) at 4 weeks. Percent improvement was 27.5% (32.3%) at 1 week
and 33.3% (33.3%) at 4 weeks. Results were similar on the HRSD-17 and
are presented in Table 3 . Comparing baseline characteristics variables
between responders and non-responders did not yield any statistically
signicant dierences ( p ≥ .05). Comparing baseline characteristics be-
tween responders at 1 week vs 4 weeks also did not yield any statistically
signicant dierences either ( p ≥ .05).
Also, since we collected daily BDI-II during treatment days, we were
able to assess trajectories of outcomes, presented in Fig. 2 . Overall, re-
sponders showed rapid improvement during the treatment week, having
achieved response on average by the end of the last day, and continued
to show slow but steady additional improvement at the 1- and 4-weeks
follow-ups ( Fig. 2 ). Analyses showed a signicant improvement in BDI-
II score over time (F2,6;54,7 = 13.5, p < .001), with planned contrasts
showing signicant improvements starting on day 2 ( p = .018) up to
3
J.-P. Miron, M. Hyde, L. Fox et al. Journal of Affective Disorders Reports 4 (2021) 100077
Fig. 2. Trajectories of improvement on the BDI-II. Responders showed rapid improvement during the accelerated course, having achieved response on average by
the end of the last day, and continued to show slow but steady additional improvement at the 1- and 4-weeks follow-ups. Use of background shading delineates the
arTMS course. BDI-II = the Beck Depression Inventory – II, arTMS = accelerated repetitive transcranial magnetic stimulation.
Table 3
Outcomes of interest.
BDI-II
Response 1 week after treatment 33.3% (10/30)
Response 4 weeks after treatment 43.3% (13/30)
Remission 1 week after treatment 13.3% (4/30)
Remission 4 weeks after treatment 30.0% (9/30)
Score baseline 35.2 (9.2)
Score change 1 week after treatment 24.0 (11.7)
Score change 4 weeks after treatment 23.5 (13.3)
Percent improvement 1 week after treatment 27.5% (32.3%)
Percent improvement 4 weeks after treatment 33.3% (33.3%)
HRSD-17
Response 1 week after treatment 36.7% (11/30)
Response 4 weeks after treatment 43.3% (13/30)
Remission 1 week after treatment 16.7% (5/30)
Remission 4 weeks after treatment 33.3% (10/30)
Score baseline 19.8 (4.5)
Score change 1
week after treatment 12.9 (6.7)
Score change 4 weeks after treatment 12.2 (7.6)
Percent improvement 1 week after treatment 37.0% (25.8%)
Percent improvement 4 weeks after treatment 40.0% (31.5%)
Data are mean (SD). For remission and response rates, data are%
of participants assessed (N). BDI-II = Beck Depression Inventory-II,
HRSD-17 = 17-item Hamilton Rating Scale for Depression.
the end of last day of treatment ( p = .002), with no further signicant
changes 1 and 4 weeks after treatment.
4. Discussion
The past three decades have seen the rise of rTMS as an eective and
well-tolerated treatment in MDD. Still, conventional once daily rTMS
regimens require frequent visits over 4–6 weeks, thus carrying a travel
burden to patients and caregivers. Accelerated protocols, if eective,
would reduce travel burden, and oer potential applicability in inpatient
or emergency settings.
Most accelerated studies to date have employed either high-
frequency or intermittent theta-burst stimulation ( Baeken et al., 2013 ;
Cole et al., 2020 ; Fitzgerald et al., 2018 ; Holtzheimer et al., 2010 ;
LOO et al., 2007 ). However, 1 Hz right DLPFC protocols have shown bet-
ter tolerability ( Kaur et al., 2019 ) and similar ecacy to high-frequency
left DLPFC protocols in a recent 300-person study on a once-daily reg-
imen ( Fitzgerald et al., 2019b ), leaving open the question of whether
1 Hz protocols may also be accelerated in a similar fashion. To date,
we are only aware of 2 trials having studied 1 Hz arTMS specically:
an initial one was completed in a small patient cohort ( N = 7) and
used a limited number of sessions (18 over 10 days) ( Tor et al., 2016 ).
More recently, our group published another 1 Hz arTMS trial, where 48
participants received 6 daily sessions of 1 Hz arTMS over 5 days (30
sessions total) ( Miron et al., 2020b ). In this study, which employed a
ring-shaped rather than gure-8 coil over F4, we reported modest re-
sponse and remission rates of 25.0% and 16.7% on the BDI-II 1 week
after treatment. Compared to that study, we modied our 1 Hz pro-
tocol to increase the number of pulses and daily sessions, in order to
potentially maximize treatment eects, switched to a standard gure-8
coil to increase generalizability, and also reassessed at 4 weeks post-
treatment without any maintenance or continuation treatment to study
if treatment eect could be maintained through time. As in our previ-
ous study, response rates at 1 week after treatment were lower than
what is usually reported in meta-analyses of standard once-daily rTMS
trials ( Lefaucheur et al., 2020 ; Miron et al., 2019 ), even though the re-
sponders subgroup had achieved response on average by the last day of
treatment ( Fig. 2 ). This changed 4 weeks after treatment, where there
was a noticeable increase in responders and remitters, reaching 43.3%
and 30.0% respectively. This sets our overall number of responders and
remitters in the same territory as to what has been reported in large
rTMS meta-analyses ( Milev et al., 2016 ). As can be seen in Fig. 2 , a linear
trend exists in responders, with improvements seen at every time points.
This is supported by our repeated measures ANOVA showing signicant
improvements already on day 2 of treatment, and maximum response
achieved on average by the end of last day of treatment, with a stabil-
ity at the 1- and 4-weeks follow-ups. The report of delayed responders
in arTMS studies are not new ( Duprat et al., 2016 ; Holtzheimer et al.,
2010 ) and have been directly raised in a recent arTMS meta-analysis
( Sonmez et al., 2019 ), but no possible explanations have been oered.
We suggest this might be related to variable individual neuroplasticity
mechanisms, which could be slower in some individuals compared to
others ( Fuchs and Flügge, 2014 ). Changes could thus manifest them-
selves at a later stage in the former group. We believe more preclinical
data are needed to oer a more denitive answer to this question. As
suggested recently ( Sonmez et al., 2019 ), future clinical trials should
4
J.-P. Miron, M. Hyde, L. Fox et al. Journal of Affective Disorders Reports 4 (2021) 100077
have longer and more robust longitudinal assessments, which could help
us identify predictors of delayed response. This would be crucial for
arTMS, since the lack of longer follow-ups in studies so far might have
led to an underestimation of the eects.
This study has several limitations. Firstly, this was an open-label
feasibility study without a sham control arm designed to obtain pilot
data for an eventual RCT, where estimates of eectiveness may be more
modest. Also, we did not reassess patients between weeks 1 and 4 af-
ter treatment, which would have allowed us to establish a more precise
trajectory of improvement. In the future, weekly or bi-weekly BDI-II
data collection during the follow-up period would be warranted. We
also used a limited number of pulses (600 per session), which is 50%
lower than what was viewed as maximally ecacious for 1 Hz stimula-
tion in a meta-analysis ( Berlim et al., 2012 ). The rationale behind this
was to keep rTMS sessions in the range of ~10 min, comparable to the
1800-pule iTBS protocol used in the recent Stanford Accelerated Intelli-
gent Neuromodulation Therapy (SAINT) rTMS study ( Cole et al., 2020 ).
Of note, 600 pulses are almost twice the amount used in the largest and
only multicenter 1 Hz RCT conducted to date ( Brunelin et al., 2014 ). In
addition, a recent RCT where high dose 1 Hz rTMS (3600 pulses) was
not shown to be more ecacious than standard dose 1 Hz rTMS (1200
pulses) ( Fitzgerald et al., 2019b ). The optimal number of pulses needed
to achieve ecacy with 1 Hz rTMS remains unknown, and future RCTs
are required to address this question. In the interim, the practical im-
pediments related to long treatment sessions include the reduced access
to rTMS. In this regard, 10 min (600 pulses) sessions have clear advan-
tages over 20 min (1200 pulses) sessions, allowing 3 to even 4 patients
to be treated every hour per machine with the former, compared to
2 patients per hour with the latter. The recent SAINT study also sug-
gested that a high number of daily sessions, spaced by 50 min intervals
in order maximize long-term potentiation (LTP) mechanisms, might be
major parameters in increasing response rates; we thus decided to fo-
cus on these aspects in our protocol ( Cole et al., 2020 ). Moreover, we
did not require participants to meet the usual requirement of treatment-
resistant depression (TRD) in our trial. However, the majority (80%)
of participants had failed at least one adequate antidepressant trial in
their current depressive episode. There was also no minimum threshold
regarding depression severity on the mood scales for study inclusion,
but average baseline scores on the BDI-II were in the severe range. Fi-
nally, the use of the self-rated BDI-II as our main outcome of interest
could be seen as a limitation. However, we also did include outcomes
on the HRSD-17 ( Table 3 ), which were similar. Self-report scales are a
good measure of patient’s perception of their own illness and recovery
( Möller, 2000 ) and the outcomes are unbiased by independent assessors
that may skew towards greater improvement in open-label studies. Fi-
nally, self-rated scales can be administered daily because of their ease
of use, allowing a more ne-grained analysis of outcome trajectories
( Fig. 2 ) ( Möller, 2000 ).
This feasibility study suggests that a signicant proportion of pa-
tients may respond rapidly to 1 Hz rTMS, when administered on an
accelerated regimen of 8 times daily for 5 days on a standard gure-8
coil. Importantly, we focused on practical considerations in order to fa-
cilitate implementation and increase accessibility. Further optimization
and validation of the treatment delivery in a formal RCT will be war-
ranted, which could take the form of a sham-controlled trial. Specially
designed rTMS coils that contain both active and sham inductors heads
are available and ensure blinding of both the patient and rTMS operator.
Various ways to optimize blinding even further are available, such as the
application of an EMLA cream or the use of surface electrodes replicating
skin sensations. An active rTMS course with a dierent protocol (HF or
iTBS) could also be oered subsequently to all non-responders, in order
to address the ethical issues of such a RCT design. Conversely, a two-arm
non-inferiority trial could also be considered, with patient either receiv-
ing active rTMS and placebo antidepressant or sham rTMS and active
antidepressant, similar to a large tDCS trial ( Brunoni et al., 2013 ). Fi-
nally, such accelerated protocols, shortening treatment courses and thus
decreasing the overall number of patients visits to an rTMS clinic, might
be a welcomed improvement in our new COVID-19 post-pandemic era.
Contributions
JPM designed the study, was responsible for data collection, an-
alyzed the data, and wrote the manuscript. MH and LF participated
in the study design, data collection, and reviewed the manuscript.
JS participated in study design, data collection and analysis, and
reviewed the manuscript. HV participated in study design and re-
viewed the manuscript. FM participated in data analysis and reviewed
the manuscript. RZ participated in data collection and reviewed the
manuscript. SD, AM, DMB, ZJD and FVR participated in the study de-
sign and reviewed the manuscript. VDJ participated in data analysis and
reviewed the manuscript. JD provided resources, supervised all phases
of the study and reviewed the manuscript.
Declaration of Competing Interest
The authors declare no nancial 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. MH, LF, HV, JS,
FM, RZ, SD, AM and VDJ do not report any conict of interest. DMB re-
ceives research support from CIHR, NIH, Brain Canada and the Temerty
Family through the CAMH Foundation and the Campbell Family Re-
search 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 Brain-
sway Ltd. He also receives in-kind equipment support from Magven-
ture for investigator-initiated research. He received medication supplies
for an investigator-initiated trial from Indivior. ZJD has received re-
search and equipment in-kind support for an investigator-initiated study
through Brainsway Inc and Magventure Inc. His-work was supported by
the Canadian Institutes of Health Research (CIHR), the National Insti-
tutes of Mental Health (NIMH) and the Temerty Family and Grant Fam-
ily and through the center for Addiction and Mental Health (CAMH)
Foundation and the Campbell Institute. FVR reports grants from Cana-
dian Institutes of Health Research, grants from Brain Canada, grants
from Vancouver Coastal Health Research Institute, grants from Michael
Smith Foundation for Health Research, personal fees from Janssen Phar-
maceuticals, in-kind equipment for investigator-initiated research from
Magventure. JD reports research grants from CIHR, the National In-
stitute of Mental Health, Brain Canada, the Canadian Biomarker Inte-
gration Network in Depression, the Ontario Brain Institute, the Weston
Foundation, the Klarman Family Foundation, the Arrell Family Founda-
tion, and the Buchan Family Foundation, travel stipends from Lundbeck
and ANT Neuro, in-kind equipment support for investigator-initiated tri-
als from MagVenture, and is an advisor for BrainCheck, TMS Neuro So-
lutions, and Restorative Brain Clinics.
Acknowledgment
JPM would like to thank the Brain & Behavior Research Founda-
tion and the Branch Out Neurological Foundation for their nancial
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. This
manuscript has been released as a pre-print at medRxiv ( Miron et al.,
2021 ).
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