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A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study
Corresponding author. Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, 1025 Queen St. W., Room B1-2107, Toronto, ON, M6J1H4, Canada.
Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, M6J1H4, CanadaDepartment of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Canada
Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, M6J1H4, CanadaCollege of Public Health, University of South Florida, Tampa, 33612, USA
Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, M6J1H4, CanadaDepartment of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Canada
Department of Psychiary, Emek Medical Center General Hospital, Afula, 1834111, IsraelFaculty of Medicine, Technion- Israel Institute of Technology, Haifa, 3525433, Israel
Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, M6J1H4, CanadaDepartment of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Canada
Department of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, CanadaSt. Michaels Hospital, Unity Health, Toronto, ON, M5B 1W8, CanadaCentre for Mental Health and Krembil Research Institute, University Health Network, Toronto, M5T 0S8, Canada
Department of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, CanadaCentre for Mental Health and Krembil Research Institute, University Health Network, Toronto, M5T 0S8, Canada
No difference in depression outcomes between once daily vs twice daily iTBS was observed after 6 weeks of treatment.
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Acceleration in response was not observed when controlling for number of pulses and operator contact.
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It is important to consider patient expectation when comparing accelerated to standard schedules of brain stimulation.
Abstract
Background
Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly.
Objective
We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS.
Methods
208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments.
Results
HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups.
Conclusions
These results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD.
]. The magnitude of the social, health, and economic burden of depression reflects, to a large degree, the limited effectiveness of current treatment options. Treatment-resistant depression (TRD), defined as failure to respond to at least 2 adequate antidepressant trials, occurs in at least 1 out of 3 patients with MDD [
Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.
]. This approach uses powerful, focused magnetic field pulses to induce lasting changes in brain activity in regions of the brain that regulate thoughts, emotions, and behavior [
Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
]. The standard rTMS protocol for TRD, initially approved by the US FDA in 2008, involves applying 10 Hz stimulation to the left dorsolateral prefrontal cortex (DLPFC). This protocol consists of 3000 pulses delivered in 4 s trains with 26 s intervals, over a period of 37.5 min [
]. Each patient typically receives a 4 to 6-week treatment course consisting of 20–30 sessions, which allows for approximately 80–130 patients to be treated per device, per year. The long treatment durations have important cost and capacity implications.
Considerable gains in the cost-effectiveness of rTMS have been achieved through the delivery of a newer form of rTMS called intermittent theta burst stimulation (iTBS) [
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
]. Multiple daily brief iTBS sessions may, in theory, enable patients to achieve remission more rapidly. This would offer major benefits both in terms of the logistics of treatment, especially for those who live far away from an rTMS centre, and in terms of the time required to achieve treatment effects, with remission achieved in days rather than weeks [
]. The speed and dosing parameters required to accelerate the response of iTBS are not known. Some early studies delivering 20 sessions of iTBS over 4 days yielded remission rates similar to a standard course of 20–30 once-daily sessions [
]. Most recently, a case series of an accelerated 5-day regimen of multiple iTBS sessions per day demonstrated safety and higher remission rates than conventional once-daily rTMS (i.e., >70% remission on all measures) [
], though the higher remission rate could have been related to the functional imaging guidance of the stimulation rather than the accelerated regimen. Among other studies employing multiple daily sessions, some have shown no evidence of accelerated response [
Two versus one high-frequency repetitive transcranial magnetic stimulation session per day for treatment-resistant depression: a randomized sham-controlled trial. Response to andrade and colleagues.
Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial.
Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression.
Taken together, these studies suggest that accelerated iTBS is feasible, tolerable, and potentially capable of achieving comparable results to that of once-daily treatment courses in a shorter time span. However, many previous studies were small, open-label designs or have lacked robust controls for several variables, such as patient expectations of rapid recovery, or the additional number of pulses, and/or sessions, in the accelerated arms. In this context, the aim of this study was to compare the efficacy and tolerability of a twice-daily iTBS versus a once-daily iTBS in patients with TRD, while controlling for number of pulses and sessions per day, and while offering a planned course length of 30 days to all patients. We hypothesized that twice-daily iTBS would result in change on the Hamilton Rating Scale for Depression-17 item (HRSD-17) [
] superior to once-daily iTBS after 10 treatment days (20 sessions compared to 10 sessions) and 30 treatment days (60 sessions compared to 30 sessions).
2. Materials and methods
2.1 Participants
The study was conducted at three Canadian academic health sciences centers (Centre for Addiction and Mental Health; University Health Network, both affiliated with University of Toronto and the University of British Columbia Hospital) after approval by their research ethics boards. All participants provided written, informed consent to participate. The trial was registered in ClinicalTrials.Gov (ID: NCT02729792).
Between April 2016 and February 2018, adult outpatients aged 18–59 who met the following criteria were recruited: voluntary and competent to consent to treatment; confirmed diagnosis of MDD, single or recurrent; failed to achieve a clinical response to an adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score ≥ 3 in the current episode [
] OR were unable to tolerate 2 separate trials of inadequate dose and duration; had a score ≥ 18 on the HRSD-17 item; had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening; able to adhere to the schedule; passed the TMS adult safety screening (TASS) questionnaire; normal thyroid functioning based on pre-study blood work.
Patients were excluded if they: had a diagnosis of substance dependence or abuse within the last 3 months; had a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump; had active suicidal intent; were pregnant; had a diagnosis of bipolar disorder, primary psychotic disorder, or current psychotic symptoms; had a diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD; had a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD; had failed a course of ECT in the current episode or previous episode (though prior history of response to ECT in a previous episode was not an exclusion); had received rTMS for any previous indication due to the potential compromise of subject blinding; had 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 except those therapeutically induced by ECT or a febrile seizure of infancy, significant head trauma with loss of consciousness for greater than 5 min; had an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth; if participating in psychotherapy, must have been in stable treatment for 3 months prior to entry into the study, with no anticipation of change in the frequency of sessions or focus over the duration of the study; had clinically significant laboratory abnormality, in the opinion of the one of the principal investigators or study physicians; currently taking more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant due to the potential to limit the effects of rTMS; had non-correctable clinically significant sensory impairment.
2.2 Procedures
Randomization and Blinding: Participants were randomized into the study, stratified by failure of at least one adequate antidepressant trial. Randomization was based on a permuted block method with a random number generator. The block sizes were fixed, and study personnel were blinded to the randomization block sizes. An independent assistant, external to the study managed the randomization of participants. Outcome assessors were blinded to treatment allocation. Participants were randomly allocated to receive once-daily (one 1200 pulse session of active iTBS and one 1200 pulse session of sham iTBS) or twice-daily treatment (two 600 pulse sessions of active iTBS spaced by approximately 54 min with two 600 pulse sessions of sham iTBS spaced by approximately 60 min) for the duration of the trial, though participants and technicians were blinded to whether they were receiving once-daily or twice-daily treatment to ensure equivalent levels of daily therapeutic contact. Sham treatments were delivered using a shielded placebo coil which reproduces auditory sensation of active stimulation. The placebo coil was placed over an area of the cortex which is not typically associated with the neurobiology of depression (i.e. corresponding to the midline Pz electrode using the 10–20 EEG system [
]). Each technician had an anterior labeled coil and a posterior labeled coil to mask the treatment allocation from the technicians. In order to ensure blinding and masking, both participants and technicians were told that the intent of the trial was to explore the effects of stimulating multiple brain regions on the effectiveness and speed of response in treating depression. Participants and technicians were told that one group would receive stimulation over one brain region in the first session and another brain region in the second and the other group would receive stimulation over two different brain regions in both the first and second sessions. They were also told that the total number of stimulations at each brain region would be the same in both groups. Importantly, participants were told that the sensation would be different for the two brain regions, specifically they were told that the anterior site, closer to the face, would feel more intense than the treatment site over the top of the head.
Study Design: Prior to treatment, participants underwent a high-resolution anatomical MRI; the first session employed real-time MRI-guided neuronavigation using the Visor 2 system (Advanced Neuro Therapeutics, Madison, WI) to position the coil at the target DLPFC region. The target location was specified by reverse co-registration from a stereotaxic coordinate on the standard Montreal neurological Institute (MNI-152) template brain, onto each individual's anatomical MRI. The MNI coordinates for left DLPFC were [x-38 y+44 z+26], drawn from a study identifying this site as optimal based on clinical outcomes and resting-state functional connectivity [
]. Neuronavigation was used for the first session to mark the treatment spot and coil orientation, subsequent treatments occurred without online neuronavigation. Additional biomarkers were collected as part of this clinical trial; these findings will be reported separately.
Each participant's resting motor threshold (RMT) was determined prior to the first treatment in accordance with previously published methods [
]. rTMS was delivered using the MagPro X100/R30 stimulator equipped with the B70 fluid-cooled coil for active left DLPFC stimulation (MagVenture, Farum, Denmark) and the placebo B70 coil for sham stimulation at the Pz site.
All participants received 30 treatment days corresponding to 60 sessions, with two sessions per day and an approximate 54-min interval between sessions in both groups (see Fig. 1). Stimulation was delivered at 120% resting motor threshold in both groups. In the twice-daily group, the first session included 600 pulses of Pz sham-iTBS stimulation immediately followed by 600 pulses of DLPFC iTBS and the second session was comprised of 600 pulses of DLPFC iTBS immediately followed by 600 pulses of Pz sham-iTBS stimulation. In the once-daily group, the first session consisted of 1200 pulses of Pz sham-iTBS stimulation, and the second sessions comprised 1200 pulses of DLPFC iTBS stimulation. The parameters of stimulation in the twice-daily group were identical (bursts of 3 pulses at 50 Hz, repeated at 5 Hz for a total of 600 pulses, with a duty cycle of 2 s on, 8 s off, over 3 min and 9 s). Thus, although both groups received 1200 pulses/day of both active and sham stimulation and 2 sessions/day in the treatment chair, in the twice-daily group the active pulses were divided into two sessions of 600 pulses about 1 h apart (Fig. 1).
Outcome measures: Clinical outcome measures were assessed at baseline prior to treatment, once every two treatment days during the first 10 treatment days, as well as after each 5 sessions of treatment up until 30 treatments, and at 1-, 4-, and 12-weeks post treatment. At each session, adverse events were self-reported; participants self-rated pain intensity of the rTMS procedure on a verbal analogue scale (from 0 [no pain] to 10 [intolerable pain]). The number of serious adverse events and reasons for treatment discontinuation when such events occurred were also reported.
The primary outcome measure was the change in HRSD-17 from baseline to day 10 of treatment while the secondary outcome measure was the change from baseline to day 30 of treatment. Additional outcome measures included: changes in the Beck Depression Inventory –II (BDI-II) [
The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
]. Remission was defined as a HRSD-17 score <8, and response was defined as a decrease in the HRSD-17 score of ≥ 50%. These outcome measures were analyzed at day 10 and day 30 of treatment.
2.3 Statistical analysis
The twice-daily iTBS protocol would be considered successful if it achieved superiority over the once-daily protocol on the HRSD-17 after 10 days of treatment. Based on the estimates of improvement rates drawn directly from our previous rTMS trial in 193 patients undergoing daily iTBS treatment [
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
] (i.e. mean change in HRSD-17 scores of 8 at 10 days, standard deviation 6.4), 172 patients (86 per arm) were needed to achieve 80% power with a 5% Type I error rate. Assuming a 15% drop out rate, we therefore aimed to randomize approximately 200 participants.
Clinical outcome analysis: For continuous outcome measures (i.e., HRSD-17, QIDS-SR16, HRSD-6, BDI-II), a linear regression was used for each of the pre-post analyses at day 10 and day 30 respectively to assess differences in clinical ratings between the two treatment groups with respect to change from baseline to the endpoint. A linear regression was used to calculate the continuous change on the HRSD-17 from baseline to 1, 4 and 12 weeks post-acute treatment to assess differences in clinical ratings between the two treatment groups. Group and the corresponding outcome measure at baseline were used as explanatory variables in the linear regression model for the continuous outcomes. For categorical outcome measures, response was defined as ≥50% reduction in symptoms and remission was defined as a post-treatment HRSD-17 < 8. Logistic regression was used for day 10 and day 30 response and remission respectively, with group and baseline HRSD-17 serving as explanatory variables. Missing data were handled using the multiple imputation method. The analyses were conducted on an intent-to-treat (ITT) basis. Supplementary analyses were also conducted for the sample of completers.
3. Results
In total, 265 participants were assessed for eligibility, of whom 57 were ineligible or declined to participate. 208 participants were randomized to receive either once-daily iTBS with 1 sham treatment (control, 1x 1200 pulses daily group) or twice-daily iTBS (accelerated, 2x 600 pulses daily group); all 208 participants received the allocated treatment. Randomization was successful with respect to the distribution of previous treatment failures across the groups. Table 1 provides the baseline demographic and clinical characteristics of the ITT sample of 208.
Table 1Baseline demographic and clinical characteristics.
Participant Characteristics
Twice daily iTBS (n = 103)
Once daily iTBS (n = 105)
Age
40.7 ± 11.1
42.1 ± 11.5
Female
66.0% (68)
60.0% (63)
Years Education
15.0 ± 2.4
15.0 ± 2.4
Left-Handed
9.7% (10)
6.7% (7)
Age of Onset
20.7 ± 10.5
21.9 ± 10.2
Currently Employed
31.1% (32)
25.7% (27)
Baseline HRSD-17
23.2 ± 4.0
23.1 ± 3.8
Baseline QIDS-SR16
17.3 ± 3.9∗
17.7 ± 3.8^
Baseline BDI-II
33.7 ± 9.37∗
35.1 ± 9.3
Episode Duration (months)
39.1 ± 50.9
35.3 ± 51.3
History of ECT in prior episode
6.8% (7)
2.9% (3)
Anxiety Comorbidity
62.1% (64)
61.0% (64)
Psychotherapy during the episode
48.5% (50)
50.5% (53)
Pharmacotherapy During Treatment
Benzodiazepine
30.1% (31)
21.9% (23)
Antidepressant
41.7% (44)
36.2% (38)
Antidepressant Combination
20.4% (21)
21.9% (23)
Antipsychotic Augmentation
20.4% (21)
20.0% (21)
Antipsychotic Alone
0% (0)
1.9% (2)
Stimulant
13.6% (14)
8.6% (9)
Lithium Augmentation
1.9% (2)
2.9% (3)
ATHF Score
7.7 ± 4.8
8.4 ± 5.3
Previous Treatment History
Unable to tolerate two trials
21.4% (22)
16.2% (17)
One Failed Antidepressant
39.8% (41)
41.9% (44)
Two Failed Antidepressants
32.0% (31.1)
22.9% (24)
Three Failed Antidepressants
18.4% (19)
17.1% (18)
Four or More Failed Antidepressants
21.4% (22)
14.3% (15)
Continuous variables are denoted as average ± standard deviation. Categorical variables are denoted as the percentage and (number) of participants in each group. HRSD-17, 17-item Hamilton Rating Scale for Depression; QIDS-SR16, 16-item Quick Inventory of Depressive Symptomatology, Self-Rated; BSI-A, Brief Symptom Inventory-Anxiety; ATHF, Antidepressant Treatment History Form; ∗n = 102, ^ n = 101.
In total, 198 participants completed the greater part of the treatments at day 10 and 185 completed the greater part of the 6 weeks of treatment. Upon weeks 1, 4, and 12 of follow up we retained 175, 157 and 141 participants respectively (see Fig. 2 for the CONSORT flow diagram for full details).
Primary outcome measure: A linear regression analysis did not reveal a significant difference in change in HRSD-17 scores from baseline to day 10 between the once-daily and twice-daily iTBS groups [t(80.08) = −0.16, p = 0.88] and when adjusting for baseline HRSD-17 score [t(74.43) = −0.21, p = 0.84]. Results revealed a significant change in HRSD-17 scores from baseline to day 10 in the twice-daily group [estimated adjusted difference −6.46 points, t(60.17) = −8.86, p = <0.001] and once-daily group [estimated adjusted difference −6.66 points, t(107.10) = −10.42, p = <0.001]. See Fig. 3 for change in clinical measures over time in the acute treatment phase.
Fig. 3Change in clinical outcome measures over time.
A. HRSD-17 mean trajectories from baseline to 30 days post treatment in participants who responded based on HRSD-17 scores at Tx 30. Accelerated N = 40, Once-daily N = 38. B. BDI-II mean trajectories from baseline to 30 days post treatment in participants who responded based on HRSD-17 scores at Tx 30. Accelerated N = 40, Once-daily N = 38. C. BDI-II mean trajectories from baseline to 30 days post treatment in participants who responded based on BDI-II scores at Tx 30. Accelerated N = 31, Once-daily N = 25. D. QIDS-SR16 mean trajectories from baseline to 30 days post treatment in participants who responded based on QIDS-SR 16 scores at Tx 30. Accelerated N = 31, Once-daily N = 25. All bars represent 95% confidence intervals. HRSD-17, 17-item Hamilton Rating Scale for Depression; BDI-II, Beck Depression Inventory –II; QIDS-SR16, 16-item Quick Inventory of Depressive Symptomatology, Self-Rated.
Secondary outcome measure: A linear regression model did not reveal a significant difference in change in HRSD-17 scores from baseline to day 30 between the once-daily or twice-daily groups [t(38.75) = 1.02, p = 0.31] and when adjusting for baseline HRSD-17 score [t(35.11) = 1.01, p = 0.32]. Results revealed a significant change in HRSD-17 scores from baseline to day 30 for both the twice-daily group [estimated adjusted difference −10.52 points, t(26.64) = −8.96, p = <0.001] and the once-daily group [estimated adjusted difference −9.05 points, t(64.52) = −10.52, p = <0.001].
Additional outcome measures day 10: Linear regression model analyses did not reveal significant group differences in change in BDI-II scores [t(89.27) = −0.89, p = 0.38] or in QIDS-SR16 scores [t(76.64) = −0.73, p = 0.47] from baseline to day 10, when adjusted for baseline scores. Results revealed a significant change in these scores from baseline to day 10 for both the twice-daily group [BDI-II: estimated adjusted difference −5.38 points, t(120.0) = −4.63, p = <0.001; QIDS-SR16: estimated adjusted difference −2.43 points, t(77.54) = −4.09, p = <0.001] and the once-daily group [BDI-II: estimated adjusted difference −6.91points, t(77.06) = −5.52, p = <0.001; QIDS-SR16: estimated adjusted difference −3.03 points, t(62.53) = −4.92, p = <0.001].
Response rates at day 10 did not differ with a rate of 12.8% (n = 94) in the twice-daily iTBS group and 20% (n = 95) in the once-daily iTBS group [t(85.67) = −1.04, p = 0.30, OR = 0.63]. Remission rates at day 10 did not differ with a rate of 5.3% (n = 94) in the twice-daily iTBS group and 4.2% (n = 95) in the once-daily iTBS group [t(64.55) = 0.39, p = 0.70, OR = 1.34].
Additional outcome measures day 30: Linear regression model analyses did not reveal a significant group difference in change in BDI-II scores [t(46.57) = 0.79, p = 0.44] or in QIDS-SR16 scores [t(45.32) = 0.17, p = 0.86] from baseline to day 30, when adjusted for baseline. However, results revealed a significant change in these scores from baseline to day 30 for both the twice-daily iTBS group [BDI-II: estimated adjusted difference in final score was −12.10 points, t(40.48) = −6.55, p = <0.001; QIDS-SR16: estimated adjusted difference in final score was −5.14 points, t(33.81) = −6.10, p = <0.001] and the once-daily iTBS group [BDI-II: estimated adjusted difference in final score was −10.17 points, t(91.63) = −6.82, p = <0.001; QIDS-SR16: estimated adjusted difference in final score was −4.96 points, t(66.24) = −7.28, p = <0.001].
Response rates at day 30 did not differ with a rate of 44.3% (n = 88) in the twice-daily iTBS group and 41.1% (n = 95) for the once-daily iTBS group [t(81.48) = 0.52, p = 0.60, odds ratio = 1.19]. Remission rates at day 30 did not differ with a rate of 22.7% (n = 88; 25.0% baseline adjusted) in the twice-daily iTBS group and 23.2% (n = 95; 24.1% baseline adjusted) in the once-daily iTBS group [t(78.36) = 0.13, p = 0.90, odds ratio = 1.05].
Longitudinal HRSD-17 at 1, 4 and 12 weeks: Linear regression analyses adjusted for baseline did not reveal a significant difference in change in HRSD-17 scores from baseline to 1 week [t(158.0) = 0.53, p = 0.60] and 4 weeks [t(102.86) = 1.90, p = 0.06] post treatment between the once-daily (n = 91 at 1 week and n = 77 at 4 weeks) and twice-daily (n = 81 at one week and n = 76 at 4 weeks) groups. Results revealed a significant difference in baseline adjusted HRSD-17 scores to 12 weeks post treatment in favor of the twice-daily (n = 67) group [estimated adjusted difference −2.53 points, t(133.44) = 2.45, p = 0.015] compared to the once-daily (n = 68) group.
Supplementary analyses were conducted for the sample of completers (n = 198). The results are similar to that of the ITT analysis and have been summarized in the supplementary documents.
4. Safety outcomes
87 of 103 participants (84%) in the twice-daily iTBS group and 91 of 105 participants (87%) in the once-daily iTBS group reported at least one side-effect during treatment (χ2 = 0.204; p = 0.65). In both groups, the most common side-effect was headache. In the twice-daily group, the median number of side-effects was 2.0 (IQR 1–4.0) and the average number of side-effects during treatment was 2.7 (SD 2.3); in the once-daily group, the median was 2.0 (IQR 1–3.0) and the average was 2.5 (2.2; F [1206] = 0.39; p = 0.531). The reported side-effects over the course of treatment are shown in Table 2. In the twice-daily group, active stimulation (i.e., the DLPFC) resulted in a median and mean pain score of 4.0 (IQR 2.7–6.0) and 4.3 (SD 2.0), respectively, while the sham stimulation (i.e., Pz electrode) median and mean pain scores were 1.0 (IQR 1.0–1.1) and 1.1 (SD 0.1), respectively. Similarly, the pain scores for the once-daily group, active stimulation resulted in a median and mean pain score of 4.3 (IQR 2.6–6.5) and 4.4 (SD 2.2), respectively, while the sham stimulation median and mean pain scores were 1.0 (IQR 1.0–1.0) and 1.0 (SD 0.2), respectively.
Table 2Adverse events.
Number of participants reporting each adverse event (%)
Twice daily iTBS (n = 103)
Once daily iTBS (n = 105)
Fishers exact p-value
Headache
72 (70%)
69 (66%)
0.555
Nausea
23 (22%)
18 (17%)
0.386
Dizziness
19 (18%)
24 (23%)
0.495
Confusion
1 (1%)
2 (2%)
1.000
Unrelated medical condition†
53 (51%)
53 (50%)
0.891
Fatigue
19 (18%)
23 (22%)
0.606
Insomnia
18 (17%)
15 (14%)
0.573
Anxiety/agitation/panic
11 (11%)
17 (16%)
0.311
Back/neck pain
8 (8%)
8 (8%)
1.000
Unrelated accident
4 (4%)
2 (2%)
0.443
Vomiting
4 (4%)
4 (4%)
1.000
Blurred Vision
3 (3%)
1 (1%)
0.367
Facial twitching/tearing
7 (7%)
3 (3%)
0.212
Tinnitus
2 (2%)
2 (2%)
1.000
Migraine
7 (7%)
7 (7%)
1.000
Abnormal Sensation
7 (7%)
6 (6%)
0.782
Facial/dental pain
15 (15%)
7 (7%)
0.074
Vivid dreams
4 (4%)
1 (1%)
0.210
iTBS = intermittent theta burst stimulation. tests for each pair of proportions.
†Predominantly common infections such as colds and flu-like conditions.
This is the first large scale clinical trial to compare the efficacy and tolerability of a twice-daily 600 pulse iTBS protocol compared to a once-daily 1200 pulse iTBS protocol in patients with TRD while also controlling for duration of contact and number of pulses per session. Contrary to our hypothesis, twice-daily iTBS did not significantly differ from once-daily treatment in terms of changes on the HRSD-17, BDI-II or QIDS-SR16, after 10 days of treatment. Furthermore, response and remission rates did not differ between the two treatment groups and the lack of difference was also apparent after 30 days. However, both once-daily and twice-daily iTBS protocols demonstrated clinically meaningful reduction in depressive symptoms and displayed good safety and tolerability profiles. However, the rates of side effects reported were slightly higher in the current trial compared to the rates found in the THREE-D trial, which used only 600 pulses of daily iTBS [
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
The findings warrant important consideration in light of the extensive effort taken to control for factors that may have influenced prior comparisons of multiple iTBS sessions. This trial employed techniques to control for the number of active and sham pulses delivered and the duration of contact with the technician across the two groups. Furthermore, both technicians and participants were not told of the primary outcome of interest timepoint after 10 days of treatment. The relatively low response and remission rates observed in both groups at this time point may reflect inherent expectation of the time course of recovery based on the scheduled 30 days of treatment. The design of the once-daily session to consist of 1200 pulses of iTBS led to a remission rate that is somewhat lower than trials that have delivered 600 pulses [
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
], which is known to suppress response and remission rates, but may also be explained by a possible cancelling of the plasticity inducing effects by extending the iTBS session [
]. In addition, our trial included TRD patients who had failed more than three antidepressant trials in the current episode and our group found that greater number of antidepressant failures is associated with lower remission rates with once daily rTMS or iTBS [
Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: an analysis from the randomised non-inferiority THREE-D trial.
]. In addition, the sample of patients included an average depressive episode greater than 3 years and approximately 1/4 of patients on benzodiazepines which may have also contributed to the somewhat lower than expected response and remission rates.
Our finding that doubling the number of sessions did not yield a more rapid improvement in symptoms, suggests that the number of sessions is not linearly related to the speed of recovery. We hypothesized that there would be clinically meaningful and statistically significant improvements after 20 sessions in the twice-daily group. Our result is consistent with another unblinded trial that compared once daily 10Hz rTMS with an accelerated protocol. The accelerated arm delivered 3 10Hz rTMS treatments per day over 3 days in week 1, 3 treatments over 2 days in week 2 and 3 treatments on a single day in week 3 [
]. In contrast, a blinded sham-controlled study comparing twice-daily with once-daily did find higher remission rates with twice-daily though no difference in change on depression scores [
Two versus one high-frequency repetitive transcranial magnetic stimulation session per day for treatment-resistant depression: a randomized sham-controlled trial. Response to andrade and colleagues.
]. We did find a statistically significant difference in favor of the twice daily group at 12 weeks post treatment. This may suggest a more durable and long-lasting effect from twice daily treatment however, this finding should be interpreted with caution as more than 1/3 of the sample had been lost to attrition at this time point.
This trial should be understood in the context of several limitations. While the rigorous attention to blinding and expectancy is useful in understanding the comparative efficacy of twice vs once-daily treatment in controlled settings, the true effect in clinical practice may be different. The design of the protocol, lasting 30 treatment days may have led to an expectancy effect and negatively biased early treatment effects. Similarly, the doubling of sessions resulted in a doubling of the prompting for side effects as these were queried at each session and may have led to over reporting of side effects and headache in particular. The current analysis also does not take into account a number of biological measures which may aid in discriminating participants who may be able to accelerate their response from those who may not be able to, in the event that the capacity for rTMS acceleration proves to be present in some but not all individuals. Similarly, the 54 min interval between sessions was chosen so as to not interfere with the potential ability to build on plasticity inducing effects of iTBS; however, this time interval may have been too long or too short for some individuals [
Despite these limitations, our findings demonstrate that doubling sessions of iTBS does not yield a more rapid reduction in depressive symptoms, nor does it lead to improved outcomes. The findings have implications for studies using greater than 600 pulses of iTBS per day and suggest that additional pulses may not have added benefits even when delivered over multiple sessions per day. These findings thus present a discrepancy with the findings of other recent studies that suggest more rapid effect, and in some cases higher remission rates, with more than two sessions per day (e.g. [
]). Resolving this discrepancy and determining the optimal number and intervals of daily sessions for iTBS, should therefore be considered a priority for future work on improving the logistics and clinical outcomes for therapeutic rTMS.
CRediT authorship contribution statement
Daniel M. Blumberger: ConceptualizationConceptualisation, Funding acquisition, Formal analysis, Writing – original draftWriting - orignal draft, conceptualized the study, acquired funding, developed the statistical analysis plan, had final responsibility for submission of the manuscript, drafted the manuscript, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Fidel Vila-Rodriguez: ConceptualizationConceptualisation, Funding acquisition, Formal analysis, Writing – original draftWriting - orignal draft, conceptualized the study, acquired funding, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Wei Wang: Formal analysis, Writing – original draftWriting - orignal draft, developed the statistical analysis plan, completed the data analysis, All authors contributed to the interpretation of data. Yuliya Knyahnytska: Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Michael Butterfield: provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Yoshihiro Noda: Funding acquisition, Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Shahak Yariv: Funding acquisition, Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Moshe Isserles: Funding acquisition, Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Daphne Voineskos: Funding acquisition, Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Nicholas J. Ainsworth: Funding acquisition, Writing – original draftWriting - orignal draft, provided medical care and performed motor thresholds for participants, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Sidney H. Kennedy: Funding acquisition, Writing – original draftWriting - orignal draft, acquired funding, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Raymond W. Lam: Funding acquisition, Writing – original draftWriting - orignal draft, acquired funding, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Zafiris J. Daskalakis: ConceptualizationConceptualisation, Funding acquisition, Formal analysis, Writing – original draftWriting - orignal draft, conceptualized the study, acquired funding, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data. Jonathan Downar: ConceptualizationConceptualisation, Funding acquisition, Formal analysis, Writing – original draftWriting - orignal draft, conceptualized the study, acquired funding, All authors contributed to critical revisions of the manuscript, All authors contributed to the interpretation of data.
Declaration of competing interest
DMB receives research support from CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he has been the site principal investigator of four sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior.
FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and Weston Brain Institute for investigator-initiated research. Philanthropic support from Seedlings Foundation. In-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in advisory board for Janssen.
WW declares no biomedical interests or conflicts.
YK declares no biomedical interests or conflicts.
MB declares no biomedical interests or conflicts.
YN has received a Grant-in-Aid for Young Scientists and Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS), research grants from Japan Agency for Medical Research and Development (AMED), investigator-initiated clinical study grants from TEIJIN PHARMA LIMITED and Inter Reha Co., Ltd. YN also receives research grants from Mochida Memorial Foundation for Medical and Pharmaceutical Research and Daiichi Sankyo Scholarship Donation Program. He has received speaker's honoraria from Dainippon Sumitomo Pharma within the past three years. He also receives equipment-in-kind support for an investigator-initiated study from Magventure Inc. And Miyuki Giken Co., Ltd.
SY receives research support from ISF (Israel Science Foundation), Minerva Stifung and BrainMarc LTD, Israel. He also received honoraria from Lundbeck, Unipharm, Medison Pharma, and serves at the advisory board of Neurolief LTD, Israel.
MI has received consulting fees from Janssen Pharmaceuticals.
DV receives support from CAMH and the Department of Psychiatry at the University of Toronto, as well as the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centers of Ontario. DV declares no biomedical interests or conflicts.
NJA declares no biomedical interests or conflicts.
SHK has research support from Abbott, Allergan, Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Ontario Brain Institute, Ontario Research Fund(ORF), Otsuka, Pfizer and Servier. He has also received consulting fees/honoraria from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund(ORF), Otsuka, Pfizer, Servier and Sunovion, and holds stock in Field Trip Health.
RWL has received ad hoc speaking/consulting fees or research grants from: Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Psychiatric Association, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, University Health Network Foundation, and VGH-UBCH Foundation.
ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work is supported by the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH), Brain Canada and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute.
JD has received research support from the Arrell Family Foundation, the Buchan Family Foundation, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Canadian Institutes of Health Research (CIHR), the Klarman Family Foundation, NIH, the Ontario Brain Institute, the Toronto General and Western Hospital Foundation, and the Weston Family Foundation; he has received travel stipends from Lundbeck and ANT Neuro; he has served as an advisor for BrainCheck, Restorative Brain Clinics, and TMS Neuro Solutions.
Acknowledgments
The study was funded by Brain Canada with the financial assistance of Health Canada, the Temerty Centre for Therapeutic Brain Intervention, Philantropic donation to the NINET lab, Seedlings Foundation, the Krembil Family Foundation, the Arrell Family Foundation, and the Toronto General and Western Hospital Foundation.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.
Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
Two versus one high-frequency repetitive transcranial magnetic stimulation session per day for treatment-resistant depression: a randomized sham-controlled trial. Response to andrade and colleagues.
Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial.
Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression.
The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: an analysis from the randomised non-inferiority THREE-D trial.
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