key: cord-0278982-3b8tt69g
authors: Miron, J.-P.; Hyde, M.; Fox, L.; Sheen, J.; Voetterl, H.; Mansouri, F.; Zhou, R.; Dees, S.; Mir-Moghtadaei, A.; Blumberger, D. M.; Daskalakis, Z. J.; Vila-Rodriguez, F.; Downar, J.
title: Evaluation of a novel 5 day accelerated 1 Hz repetitive transcranial magnetic stimulation protocol in major depression
date: 2020-09-16
journal: nan
DOI: 10.1101/2020.09.12.20193383
sha: 203d212058d4c8277d2608de0a010595b35a4b7e
doc_id: 278982
cord_uid: 3b8tt69g

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility. OBJECTIVE We assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course. METHODS We conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Depression severity was assessed on the Beck Depression Inventory-II (BDI-II) and 17-item Hamilton Rating Scale for Depression (HRSD-17). RESULTS Response and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels. CONCLUSION 1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Efficacy at the end of the course was similar to a standard daily course of 1 Hz rTMS, and there appears to be an additional delayed effect. Further validation in a randomized trial is required.

Major depressive disorder (MDD) is now the leading cause of disability worldwide, with lifetime suicide rates as high as 15%. 1, 2 Even though antidepressant medication offers convenience and simplicity of administration, discontinuation rates are close to 50% at 3 months, resulting from side-effects and lack of clinical response. 3 Repetitive transcranial magnetic stimulation (rTMS) is well established as an effective intervention in MDD, with an advantageous side-effect profile over medication. [4] [5] [6] Recent metaanalyses report response and remission rates of up to 50-55% and 30-35%, respectively. 4 Unfortunately, standard rTMS involves treatment courses over several weeks. This complicates treatment logistics for many patients who cannot take time away to attend daily clinic visits for this period of time.

To address this, accelerated rTMS (arTMS), where treatment is delivered multiple times daily, has been studied for over a decade. 7 Some evidence suggests that this approach allows comparable effectiveness to standard once-daily rTMS, while shortening treatment length. 8 novel protocol would be safe, well-tolerated, and effective, while reducing course length and accelerating clinical improvement.

We conducted a prospective, single-arm, open-label feasibility study. Adult (18-85 years of age) outpatients were included for study participation if they 1) had a Mini International Neuropsychiatric Interview (MINI) confirmed MDD diagnosis (single or recurrent episode) and 2) maintained a stable medication regimen from 4 weeks before treatment start to the end of the study. Exclusion criteria were: 1) history of substance dependence or abuse within the last 3 months; 2) concomitant major unstable medical illness; 3) cardiac pacemaker or implanted medication pump; 4) active suicidal intent; 5) diagnosis of any personality disorder as assessed by a study investigator to be primary and causing greater impairment than MDD; 6) diagnosis of any psychotic disorder; 7) any significant neurological disorder or insult (including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure confirmed diagnostically by neurological assessment [except those therapeutically induced by ECT], cerebral aneurysm, Parkinson's disease, Huntington's chorea, dementia, stroke, neurologically confirmed diagnosis of traumatic brain injury, or multiple sclerosis); 8) if participating in psychotherapy must have been in stable treatment for at least 3 months prior to entry into the study (with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study); 9) any clinically significant laboratory abnormality in the opinion of the investigator; 10) a dose of more than lorazepam 2 mg daily (or equivalent) currently (or in the last 4 weeks) or any dose of an anticonvulsant due to the potential to limit rTMS efficacy and 11) any non-correctable . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Baseline assessment was completed during the week prior to arTMS initiation and consisted of a clinical assessment by trained research staff, cap fitting, and motor threshold calibration. Participants were reassessed 1 week and 4 weeks after treatment. Participants who missed any one of the treatment days or 4 or more sessions overall were withdrawn.

Participants were asked not to change their medication regimen throughout the whole treatment, up until the 1-week reassessment.

At each clinical assessment before and after the course, participants completed the selfrated Beck Depression Inventory-II (BDI), and research staff administered the clinician-rated Hamilton Rating Scale for Depression 17-item (HRSD-17). During the course, at the beginning of each treatment day before rTMS initiation, participants also completed the BDI-II and were queried about any adverse events. Participants also completed the BDI-II immediately following their final rTMS session after the last treatment day (not done for HRSD-17). Self-rated pain intensity of the rTMS procedure was recorded on a verbal analog scale (VRS -from 0 [no pain] . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . https://doi.org/10.1101/2020.09.12.20193383 doi: medRxiv preprint to 10 [intolerable pain]). Moreover, serious adverse events and reasons for treatment discontinuation were recorded when such events occurred. Stimulation intensity was adaptively titrated upward, aiming to reach the target intensity of 120% rMT on the first session of treatment, without exceeding maximum tolerable pain. We recorded the number of sessions required to reach 120% rMT.

Outcomes of interest included score changes, percent improvement, and response and remission rates on the BDI-II. These were calculated after the end of their last day of treatment and at the 1-and 4-weeks follow-ups. These outcomes were also calculated at the 1-and 4weeks follow-ups on the HRSD-17. Response was defined as score reductions of ≥50% from baseline. Remission was defined as a score of ≤12 18 on the BDI-II and ≤7 on the HRSD-17. 19

Regarding suicidality, we assessed the number of participants who had achieved remission (number of participants who had started with a suicidality score greater than zero at baseline and who decreased to zero at reassessment). Suicidality scores were drawn from the suicide item on the BDI-II and HRSD-17.

From September 23, 2019 to February 13, 2020, 37 participants with MDD were screened for eligibility, 4 of whom were deemed ineligible or declined to participate; thus, 33 participants were enrolled and began treatment. Of these, 3 discontinued during treatment and were excluded from analysis: 2 participants lost interest and 1 participant was removed by the attending physician after reporting visual symptoms suggestive of possible retinal detachment on day 3 (subsequent diagnosis of migraine equivalent). Thus, 30 participants completed the entire study (Figure 1 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . Table 1 provides the baseline characteristics. Mean age was 43.5 ± 13.9, with 43.3% (13/30) female participants. Mean age of depression onset was 21.4 ± 9.9 years old, with the average length of current episode 13.0 ± 12.7 months. 83.3% of patients were receiving psychopharmacotherapy during the trial, with 60.0% being on at least one antidepressant during the study. All patients had tried antidepressant medication in the past, with a mean of 7.9 ± 4.0 lifetime trials. Average Antidepressant Treatment History Form (ATHF) total score was 6.6 ± 5.0. The average number of trials on the ATHF in the current episode was 1.3 ± 1.2, with 24/30 (80.0%) having had at least one adequate antidepressant trial in their current depressive episode.

Safety and tolerability outcomes are presented in Table 2 . No serious adverse events (AE) were reported. Overall, 53.3% of patients reported at least one occurrence of an AE at some point during treatment, the most commonly experienced being headache (33.3%). Pain ratings decreased from 3.5 ± 2.0 (first treatment) to 1.7 ± 1.6 (last treatment). Average rMT was 34.6 ± 7.0% of maximum stimulator output, resulting in a mean target stimulation intensity (120%) of 41.6 ± 8.5%. All patients were able to reach their target stimulation intensity, averaging 1.1 ± 0.5 sessions to do so.

BDI-II scores decreased overall from 35.2 (SD 9.2) at baseline down to 23.6 (10.5) after last treatment day, 24.0 (11.7) at 1 week, and 23.5 (13.3) at 4 weeks. Percent improvement was 32.2% (SD 27.0%) after last treatment day, 27.5% (32.3%) at 1 week, and 33.3% (33.3%) at 4 weeks. This translated into response rates of 30.0% (9/30) after last treatment day, 33.3% (10/30) at 1 week, and 43.3% (13/30) at 4 weeks; remission rates were 10.0% (3/30) after last treatment day, 13.3% (4/30) at 1 week, and 30.0% (9/30) at 4 weeks. Overall, responders showed rapid improvement during the accelerated course, having achieved response on average by the end of the last day, and continued to show slow but steady additional . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . improvement at the 1-and 4-weeks follow-ups (Figure 2) . Outcomes for HRSD-17 are presented in Table 3 .

Outcomes regarding suicidality are shown in Table 4 . At baseline, 70.0% (21/30) of total participants reported a score of at least 1 on the suicidality item of the BDI-II. On the last day of treatment, 47.6% (10/21) of these had achieved remission on the BDI-II, 52.4% (11/21) at 1

week, and 42.9% (9/21) at 4 weeks. No patients reported active suicidal intent at any point during the study.

The past three decades have seen the rise of rTMS as an effective and well-tolerated treatment in MDD. Still, conventional once-daily rTMS regimens require frequent visits over 4-6 weeks, thus carrying a travel burden to patients and caregivers. Accelerated protocols, if effective, would reduce travel burden, and offer potential applicability in inpatient or emergency settings.

Most accelerated studies to date have employed either high-frequency or intermittent theta-burst stimulation. 7,8,10,20,21 However, 1 Hz right DLPFC protocols are better-tolerated and have shown similar efficacy to high-frequency left DLPFC protocols in a recent 300-person study on a once-daily regimen 22 , leaving open the question of whether 1 Hz protocols may also be accelerated in a similar fashion. To date, we are only aware of 2 trials having studied 1 Hz arTMS specifically: an initial one was completed in a small patient cohort (N = 7) and used a limited number of sessions (18 over 10 days). 23 More recently, our group published another 1 Hz arTMS trial, where 48 participants received 6 daily sessions of 1 Hz arTMS over 5 days (30 sessions total). 12 In this study, which employed a ring-shaped rather than figure-8 coil over F4, we reported modest response and remission rates of 25.0% and 16.7% on the BDI-II 1 week after treatment.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . https://doi.org/10.1101/2020.09. 12.20193383 doi: medRxiv preprint Compared to that study, we modified our 1 Hz protocol to increase the number of pulses and daily sessions, in order to potentially maximize treatment effects, switched to a standard figure-8 coil to increase generalizability, and also reassessed at 4 weeks post-treatment without any maintenance or continuation treatment to study if treatment effect could be maintained through time. As in our previous study, response rates at 1 week after treatment were lower than what is usually reported in meta-analyses of standard once-daily rTMS trials 5,24 , even though the responders subgroup had achieved response on average by the last day of treatment (Figure 2) . This changed 4 weeks after treatment, where there was a noticeable increase in responders and remitters, reaching 43.3% and 30.0% respectively. This sets our number of responders close to and our number of remitters in the same territory as to what has been reported in large meta-analyses. 4 As can be seen in Figure 2 , a linear trend exists in responders, with additional improvements seen at every time points. This suggests a delayed effect, akin to what was reported in some arTMS trials. 7,25,26 Thus, accumulating evidence points toward the idea that it is possible to shorten rTMS treatment and eventually reach similar improvement rates as standard once-daily rTMS, however without being able to "accelerate" the effect per se in all eventual responders.

The treatment course also helped relieve suicidality in participants who presented a positive score at baseline, with close to 50% remission by the end of the last day of treatment, and over 50% at the 1-week follow-up, beyond overall depression response and remission rates. This suggests an anti-suicidal effect of rTMS that may be partially independent of mood improvement in of itself, akin to what has been reported elsewhere. 27-32 Rapid anti-suicidal effects of rTMS could prove an important area of study, especially in emergency care and inpatient settings where quick relief is needed.

This study has several limitations. Firstly, this was an open-label feasibility study without a sham control arm designed to obtain pilot data for an eventual RCT, where estimates of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . https://doi.org/10.1101/2020.09.12.20193383 doi: medRxiv preprint effectiveness may be more modest. Also, we did not reassess patients between weeks 1 and 4 after treatment, which would have allowed us to establish a more precise trajectory of improvement. In the future, weekly or bi-weekly BDI-II data collection during the follow-up period would be warranted. Also, patients were asked not to change their medication regimen up until the 1-week follow-up, with the 4 weeks follow-up having been planned as a naturalistic outcome reassessment, without expectation of a possible delayed improvement, that we ended up observing. We therefore cannot rule out that the delayed improvement might have been due to medication changes in some patients. Medication stability up until the 4-weeks follow-up point would therefore need to be part of a future RCT protocol in order to allow separate outcome analyses of patients who changed their medication before the end of the study. Furthermore, given the reports of improvement beyond the 4-week mark 25 , additional follow-ups should be planned in future studies. We also used a limited number of pulses (600 per session), which is 50% lower than what was viewed as maximally efficacious for 1 Hz stimulation in a metaanalysis. 13 The rationale behind this was to keep rTMS sessions in the range of ~10 min, comparable to the 1800-pule iTBS protocol used in a recent high-dose highly-accelerated rTMS study. 10 Additionally, even though our number of daily sessions (8) was high compared to other arTMS trials, it was still lower than the 10x daily treatment employed in that same study. So far, we are not aware of any specific rationale behind that number and thus decided to use the maximum number of sessions that would fit into a normal technician workday, without the need for overtime or overlapping teams working on different schedules. Finally, we did not require participants to meet the usual requirement of treatment-resistant depression (TRD) in our trial.

However, the majority (80%) of participants had failed at least one adequate antidepressant trial in their current depressive episode. There was also no minimum threshold regarding depression severity on the mood scales for study inclusion, but average baseline scores on the BDI-II were in the severe range.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 16, 2020. . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 16, 2020. . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. Table 3 : Changes in depression severity scores, percent improvement and response and remission rates throughout the study.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . https://doi.org/10.1101/2020.09.12.20193383 doi: medRxiv preprint Figure 2 : Trajectories of improvement on the BDI-II. Responders showed rapid improvement during the accelerated course, having achieved response on average by the end of the last day, and continued to show slow but steady additional improvement at the 1-and 4-weeks follow-ups. Use of background shading delineates the arTMS course. BDI-II = the Beck Depression Inventory -II, arTMS = accelerated repetitive transcranial magnetic stimulation.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 16, 2020. . https://doi.org/10.1101/2020.09.12.20193383 doi: medRxiv preprint

Depression Is the Leading Cause of Disability Around the World

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018)

Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes

High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression

Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression

The Role of Low-Frequency Repetitive Transcranial Magnetic Stimulation in Major Depression: A Call to Increase the Evidence Base

Evaluation of a Novel Therapeutic Repetitive Transcranial Magnetic Stimulation Technique Optimized for Increased Accessibility in Major Depression

Clinically Meaningful Efficacy and Acceptability of Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) for Treating Primary Major Depression: A Meta-Analysis of Randomized, Double-Blind and Sham-Controlled Trials

The authors declare no financial interests relative to this work. JPM reports research grants