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Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial

Authors:
  • Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health

Abstract and Figures

Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Funding: Canadian Institutes of Health Research.
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Articles
www.thelancet.com Vol 391 April 28, 2018
1683
Effectiveness of theta burst versus high-frequency repetitive
transcranial magnetic stimulation in patients with depression
(THREE-D): a randomised non-inferiority trial
Daniel M Blumberger, Fidel Vila-Rodriguez, Kevin E Thorpe, Kfir Feffer, Yoshihiro Noda, Peter Giacobbe, Yuliya Knyahnytska, Sidney H Kennedy,
Raymond W Lam, Zafiris J Daskalakis, Jonathan Downar
Summary
Background Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation
(rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based
treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered
in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical eectiveness,
safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.
Methods In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to
specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental
Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC).
Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or
could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication
doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly
allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification
by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-
label but investigators and outcome assessors were masked to treatment groups. Participants were treated with
10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The
primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a
non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all
participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This
trial is registered with ClinicalTrials.gov, number NCT01887782.
Findings Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and
209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group
were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to
13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted dierence 0·01,
lower 95% CI –1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with
treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale
3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not dier between groups (10 Hz rTMS: 13 [6%] of
205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event
was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208).
Interpretation In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment
of depression. Both treatments had low numbers of dropouts and similar side-eects, safety, and tolerability profiles.
By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times
without compromising clinical eectiveness.
Funding Canadian Institutes of Health Research.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction
Major depressive disorder is a leading cause of disability
worldwide.1 About a third of patients with major depressive
disorder do not respond to pharmacotherapy or psycho-
therapy.2 For patients with treatment-resistant depression,
non-invasive brain stimulation via techniques such as
repetitive transcranial magnetic stimulation (rTMS) is
an emerging option.3 rTMS uses powerful, focused
magnetic field pulses to induce durable changes in the
activity of brain regions that are aected by major
depressive disorder.4,5 Large-scale multicentre trials and
meta-analyses over the past 20 years have confirmed the
ecacy and safety of rTMS of the left dorsolateral
prefrontal cortex in treatment-resistant depression.6–8
Lancet 2018; 391: 1683–92
See Comment page 1639
Temerty Centre for
Therapeutic Brain Intervention
at the Centre for Addiction
and Mental Health, Toronto,
ON, Canada
(D M Blumberger MD,
Y Knyahnytska MD,
Prof Z J Daskalakis MD);
Department of Psychiatry
(D M Blumberger,
P Giacobbe MD, Y Knyahnytska,
Prof S H Kennedy MD,
Prof Z J Daskalakis,
J Downar MD), Institute of
Medical Science
(D M Blumberger,
Prof S H Kennedy,
Prof Z J Daskalakis, J Downar),
Faculty of Medicine and Dalla
Lana School of Public Health
(K E Thorpe MMath), University
of Toronto, Toronto, ON,
Canada; Non-Invasive
Neurostimulation Therapies
(NINET) Laboratory
(F Vila-Rodriguez MD) and
Department of Psychiatry
(F Vila-Rodriguez,
Prof R W Lam), University of
British Columbia, Vancouver,
BC, Canada; Applied Health
Research Centre (AHRC)
(K E Thorpe) and Li Ka Shing
Knowledge Institute
(K E Thorpe, Prof S H Kennedy),
St Michael’s Hospital, Toronto,
ON, Canada; Shalvata Mental
Health Centre, Hod-Hasharon,
Israel (K Feffer MD); Sackler
School of Medicine, Tel Aviv
University, Tel Aviv, Israel
(K Feffer); Department of
Neuropsychiatry, School of
Medicine, Keio University,
Japan (Y Noda MD); Harquail
Centre for Neuromodulation,
Sunnybrook Health Sciences
Centre, Toronto, ON, Canada
(P Giacobbe); and Centre for
Mental Health (P Giacobbe,
J Downar), MRI-Guided rTMS
Clinic (J Downar), and Krembil
Research Institute
(Prof S H Kennedy, J Downar),
University Health Network,
Toronto, ON, Canada
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Correspondence to:
Dr Daniel M Blumberger, Temerty
Centre for Therapeutic Brain
Intervention at the Centre for
Addiction and Mental Health,
Toronto, ON M6J 1H4, Canada
daniel.blumberger@camh.ca
rTMS is approved by the US Food and Drug
Administration (FDA) and is covered by many public and
private insurers in the USA and other countries. However,
adoption of this treatment has been slow, partly due to
high cost and low capacity. The conventional, FDA-
approved protocol requires 37·5 min of 10 Hz stimulation
per session.7 Long session lengths restrict treatment
capacity and increase the cost per session. Reduced
session lengths could therefore improve the accessibility
and cost-eectiveness of rTMS.
A newer form of rTMS called theta burst stimulation
(TBS) has been developed.9,10 Unlike 10 Hz stimulation,
TBS mimics endo genous theta rhythms, which can
improve induction of synaptic long-term potentiation.10
One form of TBS, intermittent TBS (iTBS), delivers
600 pulses in just 3 min, yet shows similar or more potent
excitatory eects than conventional 10 Hz stimulation.11
Several pilot trials12–14 and two meta-analyses8,15 indicate
that iTBS is superior to sham treatment for treatment-
resistant depression. However, the key practical question
is whether iTBS performs comparably to the existing
standard of care. If 3 min iTBS sessions were non-
inferior to the standard, FDA-approved 37·5 min 10 Hz
sessions, then the capacity, cost, and accessibility of rTMS
would improve several-fold, greatly improving its clinical
usefulness.
We therefore conducted a randomised, multicentre,
non-inferiority trial to compare iTBS with conventional
10 Hz rTMS in patients with treatment-resistant dep-
ression. We hypothesised that iTBS would achieve
non-inferior reductions in depressive symptoms and non-
inferior rates of response and remission compared with
the standard 10 Hz rTMS protocol. We also aimed to
compare safety and tolerability outcomes in terms of self-
reported adverse events, treatment-associated pain, and
numbers of all-cause dropouts.
Methods
Study design and participants
The study was a randomised, multicentre, non-inferiority
trial. Participants were recruited after referral to specialty
neurostimulation centres at three Canadian academic
health centres (Centre for Addiction and Mental Health,
Toronto, ON; Toronto Western Hospital, Toronto, ON;
University of British Columbia Hospital, Vancouver, BC).
We recruited adults aged 18–65 years who had a
Mini-International Neuropsychiatric Interview-confirmed
diagnosis of major depressive disorder, as a single or
recurrent episode. A patient met inclusion criteria if their
current episode showed a 17-item Hamilton Rating Scale
for Depression (HRSD-17)16 score of at least 18, they showed
no clinical response to an adequate dose of an
antidepressant (based on an antidepressant treatment
history form score of more than 3 in the current episode)
or were unable to tolerate at least two separate trials of
antidepressants of inadequate dose and duration, and
they had received a stable antidepressant regimen for at
least 4 weeks before treatment, which continued during
treatment. Exclusion criteria included substance abuse or
dependence in the past 3 months, active suicidal intent,
Research in context
Evidence before this study
We searched PubMed from Jan 1, 1996, to Dec 7, 2017, with the
search terms: “depression”, “transcranial magnetic stimulation”,
and “theta burst stimulation”. We restricted the search to reviews
and clinical trials in English. Systematic reviews and depression
guidelines have recognised repetitive transcranial magnetic
stimulation (rTMS) as an evidence-based treatment for patients
who have not responded to a minimum of one adequate
antidepressant treatment trial. In 2015, the UK National Institute
for Health and Care Excellence recommended rTMS as a
treatment for depression. Additionally, the US Agency for
Healthcare Research and Quality published a meta-analysis that
found a mean reduction in Hamilton Rating Scale for Depression
(HRSD-17) score of 4·53 points (95% CI –6·11 to –2·96) in patients
treated with rTMS compared with sham treatment. The form of
rTMS with the most supporting evidence is a high-frequency
(10 Hz) protocol, in which rTMS is delivered to the left
dorsolateral prefrontal cortex over 37·5 min. Broad access to
rTMS treatment has been partly limited by the number of
patients who can be treated with existing protocols. A newer
form of rTMS, theta burst stimulation (TBS), can be delivered in a
similar excitatory protocol to the standard 10 Hz protocol.
A treatment of excitatory intermittent TBS (iTBS) can be
delivered in slightly more than 3 min. Several small trials and two
meta-analyses have suggested that iTBS can be efficacious in
treating depression.
Added value of this study
To our knowledge, this is the largest trial of brain stimulation
ever done and is the first adequately powered non-inferiority
trial to compare the effectiveness of iTBS with that of the
standard 10 Hz treatment. Our data robustly show that iTBS
is non-inferior in reducing depressive symptoms, increasing
response (indicated by a 50% reduction in HRSD-17 score),
and achieving remission of symptoms (indicated by an
HRSD-17 score of less than 8), with very similar tolerability
and safety profiles between the two treatments.
Implications of all the available evidence
Excitatory rTMS can be delivered to the left dorsolateral prefrontal
cortex by use of an iTBS protocol with no reduction in clinical
effectiveness for major depressive disorder, compared with
standard 10 Hz rTMS treatment. A course of treatment requires
daily attendance on weekdays for 4 to 6 weeks; however,
treatment sessions can now be completed in just over 3 min. The
ability to deliver effective treatment efficiently could increase the
treatment capacity of clinics offering rTMS.
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pregnancy, bipolar disorder, any psychotic disorder or
current psychotic symptoms, previous rTMS treatment, a
lifetime history of non-response to an adequate course—
ie, a minimum of eight treatments—of electroconvulsive
therapy, personality disorder deemed to be the pri-
mary pathology, an unstable medical illness, substantial
neuro logical illness, abnormal serology, or the presence of
a cardiac pacemaker, intracranial implant, or metal in the
cranium. Participants were also excluded if they were
taking more than 2 mg lorazepam (or an equivalent) or
any anti zconvulsant or if more than three adequate
anti depressant trials had failed (determined by anti-
depressant treatment history form).17,18 Ethics approval
was granted by the research ethics boards of all three
institutions. A local data and safety monitoring board
oversaw the study. All participants provided written,
informed consent.
Randomisation and masking
Participants were randomly allocated (1:1) to groups
receiving either 10 Hz rTMS or iTBS of the left dorsolateral
prefrontal cortex. Randomisation tables of a fixed size were
made before each site started recruitment with a computer-
based algorithm that generated randomly permuted
blocks, which were stratified by study site, and groups
were balanced regarding degree of medication resistance
(more than one vs one or fewer adequate trials in which the
patient did not respond to treatment), since this variable
was previously associated with poor response to rTMS.7
The randomisation tables were used by sta outside the
study team to produce opaque, sealed envelopes, labelled
with a participant-specific randomisation identification
number and containing a treatment allocation code. After
collection of patient details and antidepressant treatment
history form score, participants were assigned a
randomisation identification number by study sta. The
randomisation identification number was obtained and
treatment allocation accessed after partici pants received
their baseline MRI by the treatment technician. Partici-
pants and treatment technicians were, by necessity, aware
of the treatment condition, but sta assessing treatment
outcomes were segregated in a dierent clinic area and
were masked to treatment condition. Participants were
instructed not to discuss their treatment allocation with
these sta or other participants.
Procedures
Before treatment, participants had high-resolution
anatomical MRIs, and each treatment session used
real-time MRI-guided neuronavigation with a Visor
neuronavigation system (ANT Neuro, Enschede,
Netherlands) for coil positioning. The left dorsolateral
prefrontal cortex target was located in each participant by
reverse co-registration from the MNI152 stereotaxic
coordinate (x–38, y+44, z+26), which was previously
identified as optimal on the basis of clini cal outcomes and
whole-brain functional connectivity.19 rTMS was delivered
with a MagPro X100 or R30 stimu lator, equipped with
a B70 fluid-cooled coil and high-performance cooler
(MagVenture, Farum, Denmark).
Each participant’s resting motor threshold (RMT) was
determined by use of visual observation in accordance
with standard clinical practice.20 10 Hz rTMS used
conventional FDA-approved parameters (120% RMT
stimulation intensity; 10 Hz frequency; 4 s on and 26 s
o; 3000 pulses per session; total duration of 37·5 min).6,7
iTBS was delivered at the same site and intensity
(120% RMT), diering only in stimulation pattern and
total number of pulses (triplet 50 Hz bursts, repeated at
5 Hz; 2 s on and 8 s o; 600 pulses per session; total
duration of 3 min 9 s).9 Initial treatment comprised
20 sessions in total, which consisted of once-daily
sessions (on weekdays; ie, five sessions a week).
An HRSD-17 score16 was determined by trained research
sta at baseline, after every five treatments, and 1 week,
4 weeks, and 12 weeks after treatment. Participants with
an improvement in HRSD-17 score of more than
30% from baseline, but who did not achieve remission,
received ten additional sessions in accord ance with
consensus guidelines.20 Participants missing scheduled
sessions because of illness or scheduling conflicts
received additional sessions at the end of the treatment
course to achieve the intended course length. However,
participants missing 4 consecutive treatment days were
withdrawn.
Secondary outcome measures were also recorded at
baseline, after every five treatments, and 1 week, 4 weeks,
and 12 weeks after treatment. These measures included
the 30-item inventory of depressive symptoms (IDS-30),21
the Brief Symptom Inventory–Anxiety Subscale (BSI-A)22
(both evaluated by the same person who assessed HRSD
scores), and the self-rated 16-item quick inventory of
depressive symptoms (QIDS-SR).23
At each session, adverse events were also self-reported;
participants self-rated pain intensity of the rTMS
procedure on a verbal analogue scale (from 1 [no pain]
to 10 [intolerable pain]). Previous rTMS trials indicate
that participants rapidly become accustomed to pain
over the initial sessions.24 Thus, 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 (appendix).
We recorded the number of sessions required to reach
120% RMT by session-end, and the number of sessions
required to start the session at this target intensity. We
also recorded the number of serious adverse events
and reasons for treatment discontinuation when such
events occurred.
Outcomes
The primary outcome was reduction in HRSD-17 score
from baseline to the end of treatment (either 20 or
30 treatments). If participants received most scheduled
sessions and a 4-week, 5-week, or 6-week assessment was
See Online for appendix
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available, they were assessed for the primary endpoint. In
the same population of participants, we also assessed
response (by HRSD-17, IDS-30, and QIDS-SR scores;
defined as score reductions of ≥50% from baseline),
remission (defined as HRSD-17 scores <8, IDS-30 scores <14,
and QIDS-SR scores <6), and improved scores on the
IDS-30, BSI-A, and the QIDS-SR as secondary outcomes.
Statistical analysis
A threshold of 3 points on the HRSD scale has been
specified by the National Institute for Health and Care
Excellence to determine a clinically meaningful dierence
between active pharmacotherapy and placebo.25,26 The
initial power analysis specified a very conservative non-
inferiority margin of 1·75 points dierence in
HRSD-17 score between iTBS and 10 Hz rTMS; this
calculation used large previous randomised control trials
of 10 Hz rTMS in treatment of depression and assumed
an endpoint HRSD-17 SD of 5 points.6,7,27,28 An interim
analysis at 100 participants revealed endpoint SDs of
about 8 points in both groups. As a result, a revised non-
inferiority margin of 2·25 points was specified to attain a
necessary sample size. Importantly, the revised non-
inferiority margin of 2·25 points was less than the lower
bound of the 95% CI of the treatment eect between
rTMS and sham on the HRSD-17, reported in a 2014
meta-analysis29 by the Agency for Healthcare Research
and Quality (mean reduction 4·53; 95% CI –6·11 to –2·96).
With this non-inferiority margin, a minimum total
sample size of 320 treatment-completers was required to
achieve 80% power at α=0·05. To account for attrition and
ensure adequate power at 1 week after treatment, we
aimed to enrol more than 400 participants.
For the primary outcome analysis, baseline-adjusted
change was estimated from an ANCOVA model, with the
final HRSD-17 score as the outcome and baseline
HRSD-17 score as the adjustment covariate, with the afore-
me ntioned non-inferiority margin of 2·25. Follow ing
standard practice for non-inferiority studies, a one-sided
test at the 5% significance level and a one-sided
95% confidence interval was computed. A per-protocol
analysis was chosen, since intention-to-treat analyses can
bias results toward non-inferiority.30 The null hypothesis
was that the baseline-adjusted mean final HRSD-17 score
for 10 Hz rTMS would be at least 2·25 points better than
for iTBS, and the alternative (non-inferiority) hypothesis
was that the baseline-adjusted mean final HRSD-17 score
for 10 Hz rTMS would be less than 2·25 points better than
for iTBS. The same non-inferiority margin of 2·25 was
used for IDS-30 and QIDS-SR secondary outcomes. A
non-inferiority margin of 15% was used to compare
proportions of responders (≥50% score improvement
from baseline on each scale). A non-inferiority margin of
10% was used to compare proportions of remitters
(within HRSD-17, IDS-30, and QIDS-SR scales). The non-
inferiority margins for response and remission were
chosen to be less than the raw mean dierence between
active and sham rTMS for response (21% dierence) and
remission (14% dier ence) that were reported in a
2014 meta-analysis.29 For tolerability comparisons, each
participant’s mean self-reported pain score across all
treatments was calculated. The prevalence and proportion
of participants reporting side-eects and adverse events
were calculated and compared with Wilcoxon rank-sum
test, Pearson’s chi-squared test, and Fisher’s exact test.
The number of treatments were compared with inde-
pendent samples t tests. The proportion of serious adverse
events in both groups was compared with a Fisher’s
exact test. R (v 3.4.3) was used for statistical analyses.
This trial is registered with ClinicalTrials.gov, number
NCT01887782.
Role of the funding source
The funder of the study (Canadian Institutes of Health
Research) and the device manufacturer (MagVenture)
that provided equipment had no role in study design,
Figure 1: Trial profile
rTMS=repetitive transcranial magnetic stimulation. iTBS=intermittent theta burst stimulation.
501 patients assessed for eligibility
87 excluded
75 did not meet inclusion criteria
12 declined to participate
414 randomly assigned to groups
205 allocated to receive 10 Hz rTMS
204 received allocated intervention
1 withdrawal before treatment
169 followed up for 1 week after treatment
150 followed up for 4 weeks after treatment
135 followed up for 12 weeks after treatment
209 allocated to receive iTBS
208 received allocated intervention
1 withdrawal before treatment
12 discontinued treatment
4 non-compliance
7 withdrawals
1 myocardial infarction
15 discontinued treatment
6 non-compliance
6 withdrawals
1 psychiatric treatment
1 withdrawal by investigator
because of agitation
1 increased suicidal ideation
192 completed 4 weeks of treatment and were
included in the primary analysis
177 included in the sensitivity analysis
176 followed up for 1 week after treatment
147 followed up for 4 weeks after treatment
129 followed up for 12 weeks after treatment
184 included in the sensitivity analysis
193 completed 4 weeks of treatment and were
included in the primary analysis
15 excluded from sensitivity analysis
1 failed electroconvulsive therapy
10 administered anticonvulsant
4 with excess benzodiazepine
9 excluded from sensitivity analysis
1 bipolar diagnosis
5 administered anticonvulsant
3 with excess benzodiazepine
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data collection, data analysis, data inter pretation, or
writing of the report. The corresponding author (DMB)
and statistician (KET) had full access to all the data and
the corresponding author (DMB) had final responsibility
for the decision to submit for publication.
Results
From Sept 3, 2013, to Oct 3, 2016, 501 participants with
major depressive disorder were enrolled, of whom
87 (17%) were ineligible or declined to participate.
414 participants were randomly assigned to receive
treatment (205 [50%] 10 Hz rTMS and 209 [50%] iTBS)
and two (one from each group) withdrew participation
after having an MRI but before receiving treatment. Of the
remaining participants, 192 (94%) participants from the
10 Hz rTMS group and 193 (92%) from the iTBS group
completed most of the course of 4 weeks of treatment
(with 12 participants from the 10 Hz rTMS group and
15 participants from the iTBS group discontinuing
treatment) and were analysed for the primary outcome
(figure 1).
13 (6%) of 205 participants in the 10 Hz rTMS group and
16 (8%) of 209 participants in the iTBS group (including
the two participants who were randomised but did
not receive treatment) discontinued treatment before
20 sessions (χ²=0·27 ; p=0·6004). Among the 10 Hz rTMS
group participants, six could not adhere to the treatment
schedule, three could not tolerate the treatment, one could
not commit to treatment, two discontinued due to lack of
perceived benefit, and one had a myocardial infarction that
led to hospital admission (deemed unrelated to the rTMS
treatment). Among the iTBS group participants, six could
not adhere to the treatment schedule, two could not
tolerate treatment, one could not commit to treatment, and
four withdrew due to lack of perceived benefit. Three
participants in the iTBS group had serious adverse events:
one with agitation that led to hospital admission, one with
worsening suicidal ideation, and one other hospital
admission for worsening depression.
Table 1 provides the baseline characteristics of the study
participants. Randomisation was successful with respect
to the distribution of participants with previous treatment
failure across groups. Training sessions across sites and
assessments of reliability across sta ratings showed
an intra-class correlation coecient of 0·996 between
HRSD scores.
HRSD-17 scores at the end of treatment showed an
estimated adjusted dierence of 0·103 points be tween
the groups (favouring iTBS), with a lower 95% CI of
–1·16 points (favouring 10 Hz rTMS treatment; table 2),
which was smaller than the non-inferiority margin of
2·25 points (p=0·0011).
On all secondary outcome measures of change in
depression scores on other inventory checklists and
response and remission rates, iTBS also showed non-
inferiority to 10 Hz rTMS, except for the reduction of
scores on the IDS-30 (table 2; figure 2).
145 (71%) of 204 participants in the 10 Hz rTMS group
and 146 (70%) of 208 participants in the iTBS group
reported at least one side-eect during treatment
(χ²=0·04; p=0·843; table 3). In both groups, the most
common side-eect was headache. In the 10 Hz rTMS
group, the median number of side-eects was 4·0 (IQR
0–8·2) and the average number of side-eects during
treatment was 5·5 (SD 6·2); in the iTBS group, the
median was 3·0 (0–8·0) and the average was 5·1 (6·4;
F [1,410]=0·65; p=0·419). The distribution of participants
reporting side-eects over the course of treatment is
shown in the appendix. The median and average pain
score across sessions was lower for 10 Hz rTMS treatment
(median 2·9, IQR 1·9–4·3; mean 3·4, SD 2·0) than for
iTBS treat ment (3·6, 2·1–5·3; 3·8, 2·0; F [1,410]=6·45;
p=0·011), although this dierence was modest. The
distribution of average pain scores among participants in
each treatment group is shown in the appendix.
10 Hz rTMS
group (n=205)
iTBS group
(n=209)
Age, years 43·2 (12·2) 41·6 (10·8)
Women 119 (58%) 127 (61%)
Men 86 (42%) 82 (39%)
Duration of education, years 16·1 (3·2) 16·4 (3·1)
Left-handed 17 (8%) 25 (12%)
Age of onset, years 21·9 (11·6) 20·3 (10·9)
In current employment 70 (34%) 80 (38%)
Baseline HRSD-17 score 23·6 (4·4) 23·7 (4·4)
Baseline QIDS-SR score 17·3 (3·9) 17·0 (5·2)
Baseline IDS-30 score 40·0 (10·3) 39·1 (9·9)
Baseline BSI-A score 10·5 (5·4) 9·8 (5·3)
Depressive episode duration, months 23·9 (28·8) 22·8 (25·7)
Previous electroconvulsive therapy 4 (2%) 16 (8%)
Anxiety comorbidity 120 (59%) 108 (52%)
Receiving psychotherapy during the
episode
79 (39%) 88 (42%)
Receiving pharmacotherapy during treatment
Benzodiazepine 71 (35%) 68 (33%)
Antidepressant 163 (80%) 155 (74%)
Antidepressant combination 48 (23%) 43 (21%)
Antipsychotic augmentation 40 (20%) 37 (18%)
Lithium augmentation 7 (3%) 6 (3%)
ATHF score 6·2 (3·3) 6·3 (3·5)
Previous treatment history
Unable to tolerate two trials 16 (8%) 16 (8%)
One failed antidepressant 92 (45%) 93 (44%)
Two failed antidepressants 59 (29%) 57 (27%)
Three failed antidepressants 38 (19%) 43 (21%)
Data are mean (SD) or number of participants in each group (% of total).
rTMS=repetitive transcranial magnetic stimulation. iTBS=intermittent theta burst
stimulation. HRSD-17=17-item Hamilton Rating Scale for Depression.
QIDS-SR=16-item Quick Inventory of Depressive Symptomatology (self-rated).
IDS-30=30-item Inventory of Depressive Symptomatology. BSI-A=Brief Symptom
Inventory-Anxiety. ATHF=Antidepressant Treatment History Form.
Table 1: Baseline demographic and clinical characteristics
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Serious adverse events were seen in one (<1%) of
205 participants in the 10 Hz group (a myocardial
infarction) and three (1%) of 209 participants in the iTBS
group (one withdrawal by the investigator because of
agitation that led to hospital admission, one participant
with worsening suicidal ideation, and one hospital
admission for worsening depression), with no significant
dierence in the number of serious adverse events
between groups (Fisher’s exact test, p=0·6232).
24 participants (15 participants from the 10 Hz rTMS
group and nine participants from the iTBS group) were
found to be ineligible for the study after discovery of
exclusionary criteria during case report form monitoring
or data cleaning at the end of the trial. Sensitivity analyses
excluding these participants also indicated non-inferiority
of iTBS for the primary outcome (table 2). Sensitivity
analyses for all primary and secondary outcomes with
ineligible participants excluded are in the appendix.
Additional prespecified analyses of HRSD-17 scores also
suggested non-inferiority of iTBS at 1 week, 4 weeks, and
12 weeks after treatment (table 2; figures 2 and 3). Further
sensitivity analyses using a one-sided 97·5% CI and a
linear mixed-eects model to account for missing data
during active treatment and follow-up phases are
presented in the appendix. Among participants who
completed a 4-week assessment, the number of treatment
sessions did not dier between the 10 Hz rTMS
(mean 26·4, SD 4·8) and iTBS (26·7, 4·7) groups
(t [1,383]=0·62; p=0·5359). 64 (33%) of 192 participants in
the 10 Hz rTMS group and 61 (32%) of 193 participants in
Number of
participants assessed
(10 Hz rTMS group/
iTBS group)
10 Hz rTMS group iTBS group Estimated
adjusted
difference
Lower 90% CI* Upper 90% CI p value
HRSD-17
Baseline 385 (192/193) 23·5 (4·4) 23·4 (4·3) ·· ·· ·· ··
After treatment 385 (192/193) 13·4 (7·8) 13·4 (7·9) 0·103 −1·16 1·36 0·0011
1 week after treatment 345 (169/176) 13·5 (8·0) 13·2 (8·1) 0·346 −1·00 1·69 0·0008
4 weeks after treatment 297 (150/147) 13·6 (7·9) 13·8 (8·5) −0·273 −1·74 1·19 0·013
12 weeks after treatment 264 (135/129) 14·1 (8·6) 13·6 (8·5) 0·349 −1·23 1·97 0·0043
Baseline (SA) 361 (177/184) 23·5 (4·3) 23·4 (4·2) ·· ·· ·· ··
After treatment (SA) 361 (177/184) 13·1 (7·6) 13·1 (7·9) −0·052 −1·35 1·25 0·0028
Response 385 (192/193) 91 (47%)† 95 (49%)† 1·83% −6·55% 10·2% 0·0005
Remission 385 (192/193) 51 (27%)† 61 (32%)† 5·21% −2·41% 12·8% 0·0005
IDS-30
Baseline 385 (192/193) 40·1 (10·5) 38·7 (9·7) ·· ·· ·· ··
After treatment 385 (192/193) 24·5 (14·5) 24·5 (14·6) −0·914 −3·07 1·25 0·15
1 week after treatment 345 (169/176) 24·5 (15·3) 23·9 (14·6) −0·135 −2·52 2·25 0·072
4 weeks after treatment 294 (149/145) 25·6 (16·6) 24·8 (15·6) −0·117 −2·89 2·66 0·1
12 weeks after treatment 263 (134/129) 24·9 (16·1) 23·2 (14·6) 0·809 −2·17 3·79 0·046
Response 385 (192/193) 76 (40%)† 76 (39%)† −0·21% −8·40% 8·00% 0·0015
Remission 385 (192/193) 49 (26%)† 48 (25%)† −0·65% −7·93% 6·60% 0·017
QIDS-SR
Baseline 384 (192/192) 17·4 (3·9) 17·0 (5·2) ·· ·· ·· ··
After treatment 379 (189/190) 10·9 (6·1) 10·6 (6·1) 0·159 −0·81 1·12 <0·0001
1 week after treatment 340 (166/174) 10·7 (6·5) 10·3 (6·1) 0·217 −0·86 1·29 <0·0001
4 weeks after treatment 286 (144/142) 11·0 (6·9) 11·0 (6·5) −0·014 −1·27 1·24 0·0018
12 weeks after treatment 264 (135/129) 11·1 (6·6) 10·9 (6·4) −0·528 −1·79 0·73 0·012
Response 379 (189/190) 76 (40%)† 76 (40%)† −0·21% −8·49% 8·10% 0·0017
Remission 379 (189/190) 37 (20%)† 50 (26%)† 6·60% −0·46% 13·70% <0·0001
BSI-A
Baseline 384 (192/192) 10·5 (5·4) 9·6 (5·3) ·· ·· ·· ··
After treatment 363 (182/181) 7·1 (5·5) 6·4 (5·1) 0·155 −1·16 1·36 <0·0001
Data for 10 Hz rTMS and iTBS are mean score (SD), unless otherwise indicated. For estimated adjusted difference values, positive values indicate a greater change in the iTBS
group and negative values indicate a greater change in the 10 Hz rTMS group. p values indicate the significance of rejecting the null hypothesis, based on the change in
symptoms in the two groups compared with the non-inferiority margin of 2·25 for change, and on a non-inferiority margin of 15% for the proportion of responders and 10% for
the proportion of remitters. rTMS=repetitive transcranial magnetic stimulation. iTBS=intermittent theta burst stimulation. HRSD-17=17-item Hamilton Rating Scale for
Depression. SA=sensitivity analysis population. IDS-30=30-item Inventory of Depressive Symptomatology. QIDS-SR=16-item Quick Inventory of Depressive Symptomatology
(self-rated). BSI-A=Brief Symptom Inventory–Anxiety Subscale. *Data are the lower 95% CI of the one-sided test for non-inferiority. †Data are n (% of participants assessed).
Table 2: Change in depression severity scores from baseline to final treatment and at follow-up, and number of participants showing response and remission
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1689
the iTBS group completed treatment—ie, achieved
remission or had less than 30% improvement—at
4 weeks (χ²=0·13; p=0·7175). The mean number of
treatment sessions given beyond 20 treatments did not
dier between the 10 Hz rTMS group (mean 9·83,
SD 0·93) and the iTBS group (9·76, 1·17; t [1,257]=0·59;
p=0·56).
Discussion
To our knowledge, this is the first randomised non-
inferiority trial comparing iTBS treatment with
10 Hz rTMS, the current standard rTMS treatment for
treatment-resistant depression. The findings provide
strong evidence that iTBS is non-inferior to standard
10 Hz rTMS in reducing depressive symptoms. Non-
inferiority was seen in clinician-rated and self-reported
measures and in continuous and categorical outcomes (ie,
change in scores and response and remission incidence).
Furthermore, the non-inferior reduction in depressive
symptoms was also observed at 1 week, 4 weeks, and
12 weeks after treatment. Self-reported adverse events and
serious adverse events did not significantly dier between
the groups. Mean pain ratings were significantly higher
for iTBS, but this result did not translate into higher
dropout rates. These findings indicate that the 3 min iTBS
protocol might serve comparably to the standard 37·5 min
10 Hz rTMS protocol as an intervention for treatment-
resistant depression.
A response rate of 49% and remission rate of
32% following iTBS treatment for treatment-resistant
depression is encouraging and clinically meaningful,
given that these participants had not responded to an
average of one to two adequate antidepressant medication
trials and about 50% of the participants had failed two
adequate trials. For comparison, the proportion of
participants who achieved remission after treatment with
switch or augmentation pharmacotherapy in the STAR*D
trial was 14·3% after two failed trials and 13% after
three failed trials.31,32 The proportions of participants
achieving remission in the 10 Hz rTMS and iTBS groups
(27% and 32%) are similar to or higher than those in the
original rTMS multicentre trials that preceded regulatory
approval (15·5–29·9%) and markedly higher than the
proportion of remissions after sham treatment in those
trials (9% and 5%).6,7 Furthermore, the overall reduction
in HRSD-17 scores (about 10·1 points in the iTBS group
and about 9·9 points in the 10 Hz rTMS group) is greater
than that reported in the sham groups of those
multicentre trials (which showed a reduction of about
3·5 points).6,7 Taken together, the response, remission,
and change in scores of participants in the 10 Hz rTMS
group would preserve assay sensitivity33 (ie, performed as
expected and would have shown ecacy compared with
sham treat ment) compared with the previous sham
results. Despite the reliable and consistent reduction in
depression symptoms observed, further eorts are
needed to identify the mechanisms of rTMS res ponse and
phenotypes that could preferentially respond to dierent
forms of stimulation34 to enhance overall outcomes.
There were no discernible dierences in self-reported
ad verse events following iTBS treatment versus
10 Hz rTMS treatment, and there was no dierence
between the groups in the number of participants
who could not complete treatment because they could
not tolerate it. Dropout rates were very low in both
groups (6–8%), particularly compared with the incidence
of discontinuation of 25% reported in a meta-analysis35 of
117 antidepressant medication trials. Mean pain scores
(out of 10 points) were 3·8 points in the iTBS group and
3·4 points for the 10 Hz rTMS group; although this
Number of participants reporting each
adverse event (%)*
10 Hz rTMS group
(n=204)
iTBS group
(n=208)
Headache 131 (64%) 136 (65%)
Nausea 22 (11%) 14 (7%)
Dizziness 8 (4%) 18 (9%)
Unrelated medical problem47 (23%) 46 (22%)
Fatigue 14 (7%) 16 (8%)
Insomnia 14 (7%) 10 (5%)
Anxiety or agitation 8 (4%) 9 (4%)
Back or neck pain 7 (3%) 6 (3%)
Unrelated accidents 2 (1%) 3 (1%)
Vomiting 1 (<1%) 1 (<1%)
Tinnitus 1 (<1%) 3 (1%)
Migraine aura 3 (1%) 4 (2%)
Abnormal sensations 2 (1%) 4 (2%)
rTMS=repetitive transcranial magnetic stimulation. iTBS=intermittent theta
burst stimulation. *p>0·05 on Fisher’s exact tests for each pair of proportions.
†Predominantly common infections such as colds and flus.
Table 3: Adverse events
Figure 2: Estimated adjusted differences in depression scores from baseline
to the end of treatment, comparing 10 Hz rTMS treatment and iTBS
treatment
Data are estimated adjusted differences with lower and upper 90% CIs. Dotted
line is the non-inferiority margin (2·25 points), determined with a one-side
lower 95% CI. iTBS=intermittent theta burst stimulation. rTMS=repetitive
transcranial magnetic stimulation. QIDS-SR=16-item Quick Inventory of
Depressive Symptomatology. IDS-30=30-item Inventory of Depressive
Symptomatology. HRSD-17=17-item Hamilton Rating Scale for Depression
(self-rated). *Data are from the sensitivity analysis population.
QIDS-SR
IDS-30
HRSD-17 at treatment end
HRSD-17 1 week after treatment
HRSD-17 4 weeks after treatment
HRSD-17 12 weeks after treatment
HRSD-17 at treatment end*
Estimated adjusted difference in score
02
5–2–
5–1 –4–314 3
10 Hz rTMS superiority
iTBS superiority
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dierence reached statistical significance, it did not
translate into increased discontinuation rates. Import-
antly, verbal analogue scale pain ratings do not account for
the duration of the participants’ reported pain, which was
about a tenth as long in the 3 min iTBS sessions compared
with the 10 Hz rTMS sessions. The pain rating observed
in this trial was somewhat higher than in other iTBS
trials; this discrepancy is probably related to the
stimulation intensity of 120% and the larger coil diameter
used in this trial.
It is important to recognise two key distinctions of
the selected parameters for iTBS. First, we did not match
the number of pulses of iTBS to the 10 Hz rTMS
(3000 pulses per session). However, previous preclinical
data suggested that doubling the number of iTBS pulses
does not strengthen the excitatory eect and might, in
fact, have an inhibitory eect.36 To avoid the risk of such a
reversal eect, and to maximise the advantage of the
shorter duration of iTBS we applied a single, standard
run of 600 pulses of iTBS.9 Second, we matched the
stimulation intensity at 120% RMT in both groups
because a previous meta-analysis37 had identified in-
adequate stimulation intensity as a potential reason
for lower ecacy in earlier rTMS trials, and current
guidelines recommend stimulation of at least 110% RMT
for conventional protocols.20,38 The original neuro-
physiological studies of iTBS used a lower intensity of
80% of the active motor threshold;9 previous pilot
studies12–14 of iTBS in major depressive disorder used
similarly low intensities, possibly because of uncertainty
over the safety of iTBS at higher intensities. TMS safety
guidelines39 recognise the paucity of data on iTBS in
non-motor regions, and do not stipulate a maximum
stimulation intensity. The data from this trial and
others40,41 indicate that iTBS could be delivered safely
at 120% RMT in prefrontal regions without reducing
tolerability.
Despite the strengths of the study, several limitations
should be considered. One limitation is the absence of a
placebo condition to blind participants to treatment
allocation. Since previous studies have addressed the
ecacy of iTBS versus sham rTMS in major depressive
disorder,12–14 our study question concerned the perform-
ance of iTBS versus the current standard of care
(10 Hz rTMS for 37·5 min) rather than versus sham.
Nonetheless, a period of sham stimulation following
active iTBS might have enabled matching of session
duration between groups. However, this would have
required delivering active and sham stimulation in
the same session, which would have unblinded the
partici pants, since active and sham rTMS are easily
distinguishable if administered to the same patient
sequentially, even with careful calibration.42 Notably,
iTBS participants received a much shorter period of
therapeutic contact than 10 Hz rTMS participants during
each session; thus, non-specific eects should have been
more powerful in the 37·5 min 10 Hz rTMS group
compared with the 3 min iTBS group. iTBS therefore
achieved non-inferiority despite the handicap of a much
shorter period of non-specific therapeutic contact. We
used a one-sided test with a 95% CI, whereas
2016 regulatory guidance recommend ations for non-
inferiority trials, released after the end of this trial, now
recommend a one-sided test with a 97·5% CI.43 To
mitigate this limitation, we have conducted a sensitivity
analysis using a one-sided test with a 97·5% CI
(appendix) and the results were not altered for any of the
primary or secondary out come findings. Another limit-
ation is the inclusion of 24 participants in the trial who
met varying exclusion criteria. These participants were
included because of sta misunderstanding or
participant information received after treatment start.
We have done sensitivity analyses to mitigate this
limitation that removed the excluded participants
and the findings were unchanged. Another potential
limitation is the use of MRI-guided neuro navigation in
every session—an approach that is not feasible or cost-
ecient for most rTMS clinics. However, we have
previously shown that the same stereotaxic target used
in this trial can be accurately localised without MRI via a
scalp-measurement-based heuristic known as BeamF3,
which has been made available in a free online tool.44
Thus, the present findings can be generalised
more broadly to rTMS clinics where MRI-guidance
is unavailable. Finally, the finding of non-inferiority
at 4 weeks and 12 weeks after treatment should be
interpreted with caution because the sample size was
reduced by attrition and because participants could alter
their medications.
In conclusion, we found that iTBS has non-inferior
eectiveness and a similar adverse event profile and
Figure 3: Change in HRSD-17 scores over time, comparing the 10 Hz rTMS and iTBS treatment groups
Data are mean scores with lower and upper 90% CIs.
Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Treatment
end
1 week after
treatment
10
Visit
15
20
25 Conditions
10 Hz rTMS
iTBS
HRSD-17 score
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1691
accept ability compared with the standard, FDA-approved
10 Hz rTMS protocol for treatment-resistant depression.
A typical iTBS treatment session (including setup)
takes about 5–10 min, compared with about 45 min for
standard 10 Hz rTMS. Therefore, the number of patients
treated per machine, per day can be tripled or quadrupled
by use of iTBS. The eectiveness of 3 min sessions
reported here could also facilitate eorts to accelerate
rTMS courses from weeks to days via several daily
sessions.45,46 More broadly, the potential for increased
capacity, improved access, reduced waiting times, and
potentially reduced costs per remission should have
a positive eect, aiding health insurers and govern-
ments in implementing wider coverage of rTMS as an
increasingly practical intervention for patients with
medication-resistant depression.
Contributors
DMB and JD conceived and designed the study. FV-R, KET, PG, SHK,
RWL, and ZJD provided input on the study design. KF, YN, and YK
provided medical care and determined the motor thresholds of
participants. DMB, KET, and JD developed the plan for statistical
analyses. KET analysed the data. All authors contributed to the
interpretation of data. DMB, FV-R, and JD drafted the manuscript.
All authors made revisions to the manuscript. DMB had final
responsibility for submission of the manuscript.
Declaration of interests
DMB reports research grants from the Canadian Institutes of Health
Research (CIHR), US National Institutes of Health, Weston Brain
Institute, Brain Canada, the Temerty Family Foundation (through the
Centre for Addiction and Mental Health Foundation and the Campbell
Research Institute), and Brainsway; reports receiving in-kind equipment
support for investigator-initiated studies (including this study)
MagVenture; is the site principal investigator for three sponsor-initiated
studies for Brainsway; and has been on an advisory board for Janssen
Pharmaceutical. FV-R reports research grants from CIHR, Brain Canada,
Michael Smith Foundation for Health Research, and Vancouver Coastal
Health Research Institute; reports receiving in-kind equipment support for
this investigator-initiated trial from MagVenture; and has been on an
advisory board for Janssen. YN reports research grants from Japan Health
Sciences Foundation, Meiji Yasuda Mental Health Foundation, and Mitsui
Life Social Welfare Foundation; and reports receiving in-kind equipment
support for another investigator-initiated study from MagVenture.
PG reports research grants from the CIHR and the US National Institutes
of Health; has been an unpaid consultant for St Jude Medical; and has
served on an advisory board for Bristol-Myers Squibb. SHK reports
research grants or consulting or speaking honoraria from Abbott
Laboratories, Allergan, AstraZeneca, Bristol-Myers Squibb, Brain Canada,
CIHR, Janssen Pharmaceutical, Lundbeck, Lundbeck Institute, the
Ontario Mental Health Foundation, Ontario Brain Institute, Ontario
Research Fund, Otsuka Pharmaceutical, Pfizer, Servier Laboratories,
St Jude Medical, Sunovion Pharmaceuticals, and Xian Janssen
Pharmaceutical. RWL reports research grants or consulting or speaking
honoraria from Akili Interactive, Asia-Pacific Economic Cooperation,
Allergan, AstraZeneca, Bristol-Myers Squibb, Canadian Depression
Research and Intervention Network, Canadian Network for Mood and
Anxiety Treatments, Johnson and Johnson, Lundbeck, Lundbeck Institute,
MagVenture, Pfizer, St Jude Medical, Otsuka, and Takeda. ZJD reports
research grants and equipment in-kind support for an investigator-initiated
study from Brainsway and Magventure. JD reports research grants from
CIHR, the National Institute for Mental Health, Brain Canada,
the Canadian Biomarker Integration Network in Depression, the Ontario
Brain Institute, the Klarman Family Foundation, the Arrell Family
Foundation, and the Edgestone Foundation; reports travel stipends from
Lundbeck and ANT Neuro; reports in-kind equipment support for this
investigator-initiated trial from MagVenture; and is an advisor for
BrainCheck. KET, KF, and YK declare no competing interests.
Acknowledgments
The authors thank the clinical research sta and the patient participants
of the THREE-D study and the local Data and Safety Monitoring Board
members. The study was partly funded by the Temerty Family
Foundation, the Grant Family Foundation, the Campbell Family Mental
Health Research Institute at the Centre for Addiction and Mental Health,
and Tina Buchan and the Buchan Family Fund (through the University
Health Network). MagVenture provided in-kind equipment support in the
form of two coils and two high performance coolers at each site; however,
MagVenture had no role in the study design, data analysis, interpretation,
or preparation of this manuscript and none of the investigators receive
any financial compensation or have any financial interests in Magventure.
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... Additionally, the DLPFC is functionally interconnected to the subgenual portion of the anterior cingulate cortex (sgACC) [5], and its modulation might affect cognitive performance in healthy people [6], patients with dementia [7] and mood disorders. For instance, the hypoactivity of the DLPFC and the anticonnectivity between the DLPFC and the sgACC have been associated with major depressive disorder [8], and both TBS and tDCS over the left DLPFC seem to be effective interventions for this condition [9,10]. ...
... The coil side was chosen based on randomized codes. This iTBS protocol was chosen because it was proven to be effective in a large depression trial [9]. ...
Article
Full-text available
Non-invasive brain stimulation (NIBS) interventions are promising for the treatment of psychiatric disorders. Notwithstanding, the NIBS mechanisms of action over the dorsolateral prefrontal cortex (DLPFC), a hub that modulates affective and cognitive processes, have not been completely mapped. We aimed to investigate regional cerebral blood flow (rCBF) changes over the DLPFC and the subgenual anterior cingulate cortex (sgACC) of different NIBS protocols using Single-Photon Emission Computed Tomography (SPECT). A factorial, within-subjects, double-blinded study was performed. Twenty-three healthy subjects randomly underwent four sessions of NIBS applied once a week: transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), combined tDCS + iTBS and placebo. The radiotracer 99m-Technetium-ethylene-cysteine-dimer was injected intravenously during the NIBS session, and SPECT neuroimages were acquired after the session. Results revealed that the combination of tDCS + iTBS increased right sgACC rCBF. Cathodal and anodal tDCS increased and decreased DLPFC rCBF, respectively, while iTBS showed no significant changes compared to the placebo. Our findings suggest that the combined protocol might optimize the activity in the right sgACC and encourage future trials with neuropsychiatric populations. Moreover, mechanistic studies to investigate the effects of tDCS and iTBS over the DLPFC are required.
... Considering the lack of sustained response to ketamine monotherapy, the combination of ketamine and rTMS was suggested. During this phase of treatment, the rTMS protocol was changed to an iTBS protocol, considering the accumulating evidence of effectiveness of iTBS in treatment resistant patients (8), as well as the advantages of shorter treatment duration in regard to cost-effectiveness (15). In view of the patient's strong response to combination treatments, as well as his history of rapid relapse, a maintenance phase was offered. ...
... Limitations of this case report include the potential effects of reduction of clonazepam doses on the response to rTMS and ketamine combination therapy; however, clonazepam had already been reduced during ketamine monotherapy, which did not lead to clinically significant effects. rTMS protocol changes from 20 Hz to TBS could be responsible for the overall improvement, although both are thought to have similar effects (8), and switching between modalities was recently shown to only bring about modest additional improvement (31). The addition of pramipexole during the maintenance phase of the patient's combination therapy may have contributed to sustained remission; however, the patient had received this medication in the past without any benefits, and the doses used we far below what is proposed for TRD (32). ...
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2022) Transcranial magnetic stimulation and intravenous ketamine combination therapy for treatment-resistant bipolar depression: A case report. Front. Psychiatry 13:986378. About a third of patients suffering from major depression develop treatment-resistant depression (TRD). Although repetitive transcranial magnetic stimulation (rTMS) and intravenous ketamine have proven effective for the management of TRD, many patients remain refractory to treatment. We present the case of a patient suffering from bipolar TRD. The patient was referred to us after failure to respond to first-and second-line pharmacotherapy and psychotherapy. After minimal response to both rTMS and ketamine alone, we attempted a combination rTMS and ketamine protocol, which led to complete and sustained remission. Various comparable and complimentary mechanisms of antidepressant action of ketamine and rTMS are discussed, which support further study of this combination therapy. Future research should focus on the feasibility, tolerability, and efficacy of this novel approach.
... All healthy controls had no history of any psychiatric disorder, confirmed by trained assessors in a clinical interview; had a 17-item HRSD score of ≤ 8; and were not currently (or in the last four weeks) on any psychotropic medication, or medication that could significantly affect brain perfusion or activity. For additional details on subject recruitment and a full list of inclusion and exclusion criteria, see 102 . ...
Article
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The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation.
... Theta burst stimulation (TBS), a patterned form of rTMS, is an FDA approved therapy for treatment resistant depression (TRD). However, reported effect sizes and response rates are heterogeneous [2]. Recent research suggests that the diversity of the induced electric fields (EF) in the brain due to individual differences in head morphology may partly explain the response variation to TMS [3]. ...
... Although there is increasing interest in using functional connectivity to inform target site selection in basic research settings (Eldaief et al., 2011;Halko et al., 2014;Lynch et al., 2019; and for TMS interventions (Cash et al., 2019;Cole et al., 2022;Fox et al., 2012;Klooster et al., 2022;Siddiqi et al., 2022), most conventional TMS protocols are not guided by the individual patient's functional brain organization. Instead, generic coil placements based on scalp heuristics (Beam et al., 2009;Mir-Moghtadaei et al., 2022) or stereotaxic coordinates derived from group-average functional maps (Blumberger et al., 2018;Weigand et al., 2018) have been used. One reason for these generic approaches is that reliable mapping of functional networks at the individual level can require large quantities of data per subject when using traditional single-echo fMRI methods (Gordon et al., 2017a;Laumann et al., 2015;Lynch et al., 2020a), which is a significant obstacle in clinical settings. ...
Article
Full-text available
Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient’s unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and in vivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource.
... After these assessments, we collected an anatomical brain scan of the participants in a 3-Tesla Magnetic Resonance Imaging (MRI) equipment (General Electric PET/MRI equipment). In the following days, a neuronavigation procedure (Brainsight, Rogue Resolutions, Inc) was performed, in which we found the left and right DLPFC according to the MNI coordinates x = -38, y = +44, y = +26, per previous studies (Blumberger et al., 2018;Fox et al., 2012). ...
Article
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Non-invasive brain stimulation (NIBS) techniques have been increasingly used over the dorsolateral prefrontal cortex (DLPFC) to enhance working memory (WM) performance. Notwithstanding, NIBS protocols have shown either small or inconclusive cognitive effects on healthy and neuropsychiatric samples. Therefore, we assessed working memory performance and safety of transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and both therapies combined vs placebo over the neuronavigated left DLPFC of healthy participants. Twenty-four subjects were included to randomly undergo four sessions of NIBS, once a week: tDCS alone, iTBS alone, combined protocol and placebo. The 2-back task and an adverse effect scale were applied after each NIBS session. Results revealed a significantly faster response for iTBS (b= -21.49, p= 0.04), but not for tDCS and for the interaction tDCS vs. iTBS (b= 13.67, p= 0.26 and b= 40.5, p= 0.20, respectively). No changes were observed for accuracy and no serious adverse effects were found among protocols. Although tolerable, an absence of synergistic effects for the combined protocol was seen. Nonetheless, future trials accessing different outcomes for the combined protocols, as well as studies investigating iTBS over the left DLPFC for cognition and exploring sources of variability for tDCS are encouraged.
Article
Objective Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation. Y.Z. Huang et al. developed the first neuromodulation model to explain the bidirectional effects of theta-burst stimulation (TBS) based on the postsynaptic intracellular calcium concentration elevation. However, we discover that the published computer code is not consistent with the model formulation, neither do the parameters and derived plots consequently match the formulations. Here we intend to fix the computer code and re-calibrate the model. Methods We corrected the affected difference equations and re-calibrated the revised model with experimental data using non-convex optimisation based on a L2 penalty. Results The revised model outperforms the initial model in characterising the relative motor-evoked potential levels of TBS-induced after-effects in various conditions. Conclusions We corrected the inconsistencies in the previous model and computer code and provided a complete calibration to support the research that is based on it. Significance This work improves the accuracy and secures the scope of the model, which is necessary to retain a rich body of research resulting from the model. Furthermore, this model provides both a quantitative model for several parameters of TBS and a basic model foundation for future refinement.
Article
Importance Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes. Objective To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD. Design, Setting, and Participants In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials. Interventions Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS. Main Outcomes and Measures The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed. Results A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI −0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ ² = 2.2). Conclusions and Relevance In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD. Trial Registration ClinicalTrials.gov Identifier: NCT02998580
Article
Description: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations. Methods: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis. Recommendations: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.
Article
Mental health disorders and substance use disorders are a leading cause of morbidity and mortality worldwide and one of the most important challenges for public health systems. While evidence-based psychotherapy is generally pursued to address mental health challenges, psychological change is often hampered by non-adherence to treatments, relapses, and practical barriers (e.g., time, cost). In recent decades, Non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to directly target dysfunctional neural circuitry and promote long-lasting plastic changes. While the therapeutic efficacy of NIBS protocols for mental illnesses has been established, neuromodulatory interventions might also be employed to support the processes activated by psychotherapy. Indeed, combining psychotherapy with NIBS might help tailor the treatment to the patient’s unique characteristics and therapeutic goal, and would allow more direct control of the neuronal changes induced by therapy. Herein, we overview emerging evidence on the use of NIBS to enhance the psychotherapeutic effect, while highlighting the next steps in advancing clinical and research methods toward personalized intervention approaches.
Article
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Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Neurostimulation Treatments" is the fourth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. Conclusions: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.
Article
Objective: To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). Participants: Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. Evidence: The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. Consensus process: In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." Conclusions: Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.
Article
Theta burst stimulation (TBS) has been proposed as a novel treatment for major depression (MD). However, randomized and sham-controlled trials (RCTs) published to date have yielded heterogeneous clinical results and we have thus carried out the present systematic review and exploratory meta-analysis of RCTs to evaluate this issue. We searched the literature for RCTs on TBS for MD from January 2001 through September 2016 using MEDLINE, EMBASE, PsycINFO, and CENTRAL. We then performed a random-effects meta-analysis with the main outcome measures including pre-post score changes in the Hamilton Depression Rating Scale (HAM-D) as well as rates of response, remission and dropout. Data were obtained from 5 RCTs, totalling 221 subjects with MD. The pooled Hedges' g for pre-post change in HAM-D scores was 1.0 (p = 0.003), indicating a significant and large-sized difference in outcome favouring active TBS. Furthermore, active TBS was associated with significantly higher response rates when compared to sham TBS (35.6% vs. 17.5%, respectively; p = 0.005), although the groups did not differ in terms of rates of remission (18.6% vs. 10.7%, respectively; p = 0.1) and dropout (4.2% vs. 7.8%, respectively; p = 0.5). Finally, subgroup analyses indicated that bilateral TBS and unilateral intermittent TBS seem to be the most promising protocols. In conclusion, although TBS is a promising novel therapeutic intervention for MD, future studies should identify more clinically-relevant stimulation parameters as well as neurobiological predictors of treatment outcome, and include larger sample sizes, active comparators and longer follow-up periods.
Article
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.
Article
Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like to other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial-magnetic-stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.