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Evaluation of a novel 5 day accelerated 1 Hz repetitive transcranial magnetic stimulation protocol in major depression

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Abstract

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness 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 figure-of-eight coil at 120% of the resting motor threshold (rMT). Depression severity was assessed on the Beck Depression Inventory-II (BDI-II) and 17-item Hamilton Rating Scale for Depression (HRSD-17). 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 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. Efficacy at the end of the course was similar to a standard daily course of 1 Hz rTMS, and there appears to be an additional delayed effect. Further validation in a randomized trial is required.
Evaluation of a novel 5 day accelerated 1 Hz repetitive transcranial magnetic stimulation
protocol in major depression
Jean-Philippe Miron 1,2,3,4,*, Molly Hyde 4,ɣ, Linsay Fox 4,ɣ, Jack Sheen 2,4, Helena Voetterl 4,5,
Farrokh Mansouri 2,4, Ryan Zhou 4, Sinjin Dees 6, Arsalan Mir-Moghtadaei 2,4, Daniel M.
Blumberger 2,3,7, Zafiris J. Daskalakis 2,3,7,8, Fidel Vila-Rodriguez 9, Jonathan Downar 2,3
1 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;
2 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
3 Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
4 Krembil Research Institute, University Health Network, Toronto, ON, Canada;
5 Department of Cognitive Neuroscience, Maastricht University, Maastricht, Limburg,
Netherlands;
6 Faculty of Engineering, McMaster University, Hamilton, ON, Canada;
7 Temerty Centre for Therapeutic Brain Intervention at the Centre for Addiction and Mental
Health, Toronto, ON, Canada;
8 Department of Psychiatry, University of California San Diego, San Diego, California, USA;
9 Non-Invasive Neurostimulation Therapies Laboratory, Department of Psychiatry, University of
British Columbia, Vancouver, BC, Canada.
ɣ Equal authorship
* Corresponding author
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MANUSCRIPT WORD COUNT: XXXX
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
BACKGROUND
Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major
depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks.
Shorter rTMS courses retaining similar effectiveness 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 figure-of-eight coil at 120% of the resting
motor threshold (rMT). Depression severity was assessed on the Beck Depression Inventory-II
(BDI-II) and 17-item Hamilton Rating Scale for Depression (HRSD-17).
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 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. Efficacy at
the end of the course was similar to a standard daily course of 1 Hz rTMS, and there appears to
be an additional delayed effect. Further validation in a randomized trial is required.
ClinicalTrials.gov Identifier: NCT04376697
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INTRODUCTION
Major depressive disorder (MDD) is now the leading cause of disability worldwide, with
lifetime suicide rates as high as 15%. 1,2 Even though antidepressant medication offers
convenience and simplicity of administration, discontinuation rates are close to 50% at 3
months, resulting from side-effects and lack of clinical response. 3
Repetitive transcranial magnetic stimulation (rTMS) is well established as an effective
intervention in MDD, with an advantageous side-effect profile over medication. 4–6 Recent meta-
analyses report response and remission rates of up to 50-55% and 30-35%, respectively. 4
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 delivered multiple times
daily, has been studied for over a decade. 7 Some evidence suggests that this approach allows
comparable effectiveness to standard once-daily rTMS, while shortening treatment length. 8
Recently, high-dosage highly-accelerated and personalized intermittent theta-burst (iTBS)
arTMS feasibility studies have reported remission rates of up to ~90%, while delivering
treatment over only 5 days. 9,10
However, arTMS has not been well studied for 1 Hz protocols. 11,12 On conventional
once-daily regimens, 1 Hz has shown superiority over sham, with some studies also suggesting
similar efficacy to HF. 4–6,11,13 1 Hz also offers several potential advantages over HF, including
less seizure risks 14,15, better tolerability 16, and the potential for implementation on simpler,
lower-cost equipment 11,12, thus possibly 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
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novel protocol would be safe, well-tolerated, and effective, while reducing course length and
accelerating clinical improvement.
METHODS
Participants
We conducted a prospective, single-arm, open-label feasibility study. 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. 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 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; 11) any non-correctable clinically
significant sensory impairment and 12) any significant cardiovascular or metabolic disorder or
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insult including, but not limited to: coronary artery disease, abnormal heart rhythms, heart
failure, cardiac valve disease, congenital heart disease, cardiomyopathy, vascular disease,
dyslipidemia, diabetes, or hypertension. All participants provided informed consent and this
study was approved by the Research Ethics Board of the University Health Network.
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 (pmid: 28541649). Treatment consisted of an arTMS course of 8 hourly
sessions per day over 5 consecutive weekdays (Monday through Friday), thus totaling 40
sessions in five days. Each rTMS session consisted 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 approximating the F4 EEG site. 17
Baseline assessment was completed during the week prior to arTMS initiation and
consisted of a clinical assessment by trained research staff, cap fitting, and motor threshold
calibration. Participants were reassessed 1 week and 4 weeks after treatment. Participants who
missed any one of the treatment days or 4 or more sessions overall were withdrawn.
Participants were asked not to change their medication regimen throughout the whole
treatment, up until the 1-week reassessment.
At each clinical assessment before and after the course, participants completed the self-
rated Beck Depression Inventory-II (BDI), and research staff administered the clinician-rated
Hamilton Rating Scale for Depression 17-item (HRSD-17). During the course, at the beginning
of each treatment day before rTMS initiation, participants also completed the BDI-II and were
queried about any adverse events. Participants also completed the BDI-II immediately following
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their final rTMS session after the last treatment day (not done for HRSD-17). 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 first session of
treatment, without exceeding maximum tolerable pain. We recorded the number of sessions
required to reach 120% rMT.
Outcomes
Outcomes of interest included score changes, percent improvement, and response and
remission rates on the BDI-II. These were calculated after the end of their last day of treatment
and at the 1- and 4-weeks follow-ups. These outcomes were also calculated at the 1- and 4-
weeks follow-ups on the HRSD-17. Response was defined as score reductions of 50% from
baseline. Remission was defined as a score of 12 18 on the BDI-II and 7 on the HRSD-17. 19
Regarding suicidality, we assessed the number of participants who had achieved remission
(number of participants who had started with a suicidality score greater than zero at baseline
and who decreased to zero at reassessment). Suicidality scores were drawn from the suicide
item on the BDI-II and HRSD-17.
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
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on day 3 (subsequent diagnosis of migraine equivalent). Thus, 30 participants completed the
entire study (Figure 1).
Table 1 provides the baseline characteristics. Mean age was 43.5 ± 13.9, with 43.3%
(13/30) female participants. Mean age of depression 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. All patients had tried antidepressant medication in the past, with a mean of 7.9 ± 4.0
lifetime trials. 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 at least one occurrence of an AE at
some point during treatment, the most commonly experienced being headache (33.3%). Pain
ratings decreased from 3.5 ± 2.0 (first treatment) to 1.7 ± 1.6 (last treatment). Average rMT was
34.6 ± 7.0% of maximum stimulator output, resulting 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.
BDI-II scores decreased overall from 35.2 (SD 9.2) at baseline down to 23.6 (10.5) after
last treatment day, 24.0 (11.7) at 1 week, and 23.5 (13.3) at 4 weeks. Percent improvement was
32.2% (SD 27.0%) after last treatment day, 27.5% (32.3%) at 1 week, and 33.3% (33.3%) at 4
weeks. This translated into response rates of 30.0% (9/30) after last treatment day, 33.3%
(10/30) at 1 week, and 43.3% (13/30) at 4 weeks; remission rates were 10.0% (3/30) after last
treatment day, 13.3% (4/30) at 1 week, and 30.0% (9/30) at 4 weeks. Overall, responders
showed rapid improvement during the accelerated course, having achieved response on
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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 (Figure 2). Outcomes for HRSD-17 are
presented in Table 3.
Outcomes regarding suicidality are shown in Table 4. At baseline, 70.0% (21/30) of total
participants reported a score of at least 1 on the suicidality item of the BDI-II. On the last day of
treatment, 47.6% (10/21) of these had achieved remission on the BDI-II, 52.4% (11/21) at 1
week, and 42.9% (9/21) at 4 weeks. No patients reported active suicidal intent at any point
during the study.
DISCUSSION
The past three decades have seen the rise of rTMS as an effective 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
effective, would reduce travel burden, and offer potential applicability in inpatient or emergency
settings.
Most accelerated studies to date have employed either high-frequency or intermittent
theta-burst stimulation. 7,8,10,20,21 However, 1 Hz right DLPFC protocols are better-tolerated and
have shown similar efficacy to high-frequency left DLPFC protocols in a recent 300-person
study on a once-daily regimen 22, 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 specifically: an initial one was completed in a small patient cohort (N = 7) and used a
limited number of sessions (18 over 10 days). 23 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). 12 In this study, which employed a ring-shaped rather than figure-8 coil over F4,
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we reported modest response and remission rates of 25.0% and 16.7% on the BDI-II 1 week
after treatment.
Compared to that study, we modified our 1 Hz protocol to increase the number of pulses
and daily sessions, in order to potentially maximize treatment effects, switched to a standard
figure-8 coil to increase generalizability, and also reassessed at 4 weeks post-treatment without
any maintenance or continuation treatment to study if treatment effect could be maintained
through time. As in our previous study, response rates at 1 week after treatment were lower
than what is usually reported in meta-analyses of standard once-daily rTMS trials 5,24, even
though the responders subgroup had achieved response on average by the last day of
treatment (Figure 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
number of responders close to and our number of remitters in the same territory as to what has
been reported in large meta-analyses. 4 As can be seen in Figure 2, a linear trend exists in
responders, with additional improvements seen at every time points. This suggests a delayed
effect, akin to what was reported in some arTMS trials. 7,25,26 Thus, accumulating evidence
points toward the idea that it is possible to shorten rTMS treatment and eventually reach similar
improvement rates as standard once-daily rTMS, however without being able to “accelerate” the
effect per se in all eventual responders.
The treatment course also helped relieve suicidality in participants who presented a
positive score at baseline, with close to 50% remission by the end of the last day of treatment,
and over 50% at the 1-week follow-up, beyond overall depression response and remission
rates. This suggests an anti-suicidal effect of rTMS that may be partially independent of mood
improvement in of itself, akin to what has been reported elsewhere. 2732 Rapid anti-suicidal
effects of rTMS could prove an important area of study, especially in emergency care and
inpatient settings where quick relief is needed.
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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
effectiveness may be more modest. Also, we did not reassess patients between weeks 1 and 4
after 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. Also, patients were asked not to change their medication regimen up until
the 1-week follow-up, with the 4 weeks follow-up having been planned as a naturalistic outcome
reassessment, without expectation of a possible delayed improvement, that we ended up
observing. We therefore cannot rule out that the delayed improvement might have been due to
medication changes in some patients. Medication stability up until the 4-weeks follow-up point
would therefore need to be part of a future RCT protocol in order to allow separate outcome
analyses of patients who changed their medication before the end of the study. Furthermore,
given the reports of improvement beyond the 4-week mark 25, additional follow-ups should be
planned in future studies. We also used a limited number of pulses (600 per session), which is
50% lower than what was viewed as maximally efficacious for 1 Hz stimulation in a meta-
analysis. 13 The rationale behind this was to keep rTMS sessions in the range of ~10 min,
comparable to the 1800-pule iTBS protocol used in a recent high-dose highly-accelerated rTMS
study. 10 Additionally, even though our number of daily sessions (8) was high compared to other
arTMS trials, it was still lower than the 10x daily treatment employed in that same study. So far,
we are not aware of any specific rationale behind that number and thus decided to use the
maximum number of sessions that would fit into a normal technician workday, without the need
for overtime or overlapping teams working on different schedules. Finally, 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
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severity on the mood scales for study inclusion, but average baseline scores on the BDI-II were
in the severe range.
In conclusion, this feasibility study suggests that a significant proportion of patients may
respond rapidly to 1 Hz rTMS, when administered on an accelerated regimen of 8 times daily for
5 days on a standard figure-8 coil. Further optimization of the treatment delivery may be
warranted, such as increasing the number of pulses per session or the number of sessions per
day. Delayed effects may be emergent in some patients on this regimen. Because of the
excellent safety and tolerability and lower equipment cost for 1 Hz stimulation, an important
question for future work will be whether accelerated 1 Hz regimens can match the efficacy of
high-frequency or iTBS protocols delivered on the same schedule. A future randomized
controlled trial directly comparing these two forms of arTMS will be important and could
potentially improve the ability of patients to access accelerated rTMS in a wider variety of care
settings. Finally, 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.
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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. MH, LF, HV, JS,
FM, RZ, SD, and AM 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 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 reports grants from Canadian 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 Pharmaceuticals, in-kind
equipment for investigator-initiated research from Magventure. 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.
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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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DOI: 10.1016/j.jpsychires.2020.03.016.
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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)preprint The copyright holder for thisthis version posted September 16, 2020. ; https://doi.org/10.1101/2020.09.12.20193383doi: medRxiv preprint
Age, years
43.5 (13.9)
Women
43.3%
Education, years
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%
Number of past antidepressant trials, lifetime
7.9 (4.0)
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
Rating Scale for Depression, ATHF = Antidepressant Treatment
History Form.
Table 1: Baseline demographic and clinical characteristics (n =
30).
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Serious AE
0/30 (0.0%)
AE total
16/30 (53.3%)
Headache
10/30 (33.3%)
Fatigue
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 adverse events (AE - %). For
pain, data mean (SD). VRS = Verbal Rating Scale.
Table 2: Adverse events.
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35.2 (9.2)
23.6 (10.5)
24.0 (11.7)
23.5 (13.3)
32.2% (27.0%)
27.5% (32.3%)
33.3% (33.3%)
30.0% (9/30)
33.3% (10/30)
43.3% (13/30)
10.0% (3/30)
13.3% (4/30)
30.0% (9/30)
19.8 (4.5)
12.9 (6.7)
12.2 (7.6)
37.0% (25.8%)
40.0% (31.5%)
36.7% (11/30)
43.3% (13/30)
16.7% (5/30)
33.3% (10/30)
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.
Table 3: Changes in depression severity scores, percent improvement and
response and remission rates throughout the study.
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BDI-II
Remission last treatment day
10/21 (47.6%)
Remission 1 week after treatment
11/21 (52.4%)
Remission 4 weeks after treatment
9/21 (42.9%)
HRSD-17
Remission 1 week after treatment
16/24 (66.7%)
Remission 4 weeks after treatment
14/24 (58.3%)
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 4: Remission rates regarding suicidality.
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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)preprint The copyright holder for thisthis version posted September 16, 2020. ; https://doi.org/10.1101/2020.09.12.20193383doi: medRxiv preprint
37 patients assessed for eligibility
4 excluded
2 did not meet inclusion criteria
2 declined to participate
33 patients enrolled
3 patients started and discontinued
treatment
2 participants lost interest
1 participant removed because of
concerning visual symptoms
30 patients completed the
treatment course and were
included in the analysis
30 patients followed up at 1-month
Figure 1: Trial CONSORT flow diagram.
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Figure 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.
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... 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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Importance: Although several strategies of repetitive transcranial magnetic stimulation (rTMS) have been investigated as treatment of major depressive disorder (MDD), their comparative efficacy and acceptability is unknown. Objective: To establish the relative efficacy and acceptability of the different modalities of rTMS used for MDD by performing a network meta-analysis, obtaining a clinically meaningful treatment hierarchy. Data sources: PubMed/MEDLINE, EMBASE, PsycInfo, and Web of Science were searched up until October 1, 2016. Study selection: Randomized clinical trials that compared any rTMS intervention with sham or another rTMS intervention. Trials performing less than 10 sessions were excluded. Data extraction and synthesis: Two independent reviewers used standard forms for data extraction and quality assessment. Random-effects, standard pairwise, and network meta-analyses were performed to synthesize data. Main outcomes and measures: Response rates and acceptability (dropout rate). Remission was the secondary outcome. Effect sizes were reported as odds ratios (ORs) with 95% CIs. Results: Eighty-one studies (4233 patients, 59.1% women, mean age of 46 years) were included. The interventions more effective than sham were priming low-frequency (OR, 4.66; 95% CI, 1.70-12.77), bilateral (OR, 3.96; 95% CI, 2.37-6.60), high-frequency (OR, 3.07; 95% CI, 2.24-4.21), θ-burst stimulation (OR, 2.54; 95% CI, 1.07-6.05), and low-frequency (OR, 2.37; 95% CI, 1.52-3.68) rTMS. Novel rTMS interventions (accelerated, synchronized, and deep rTMS) were not more effective than sham. Except for θ-burst stimulation vs sham, similar results were obtained for remission. All interventions were at least as acceptable as sham. The estimated relative ranking of treatments suggested that priming low-frequency and bilateral rTMS might be the most efficacious and acceptable interventions among all rTMS strategies. However, results were imprecise and relatively few trials were available for interventions other than low-frequency, high-frequency, and bilateral rTMS. Conclusions and relevance: Few differences were found in clinical efficacy and acceptability between the different rTMS modalities, favoring to some extent bilateral rTMS and priming low-frequency rTMS. These findings warrant the design of larger RCTs investigating the potential of these approaches in the short-term treatment of MDD. Current evidence cannot support novel rTMS interventions as a treatment for MDD. Trial registration: clinicaltrials.gov Identifier: PROSPERO CRD42015019855.