- Email: [email protected]
Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial
Brain Stimulation xxx (xxxx) xxx
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation
Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial a b s t r a c t Keywords: Repetitive transcranial magnetic stimulation (rTMS) Dorsomedial prefrontal cortex (DMPFC) Major depressive disorder (MDD)
Background: Dorsomedial prefrontal cortex (DMPFC) repetitive transcranial magnetic stimulation (rTMS) is a novel intervention for treatment-refractory depression (TRD). To date, many open-label case series and one randomized controlled trial of modest sample size have provided preliminary evidence that DMPFC-rTMS is an effective treatment for TRD. Here, we report the results of a large, doubleblinded, sham-controlled trial of DMPFC-rTMS for TRD. Objective: The primary aim of this study was to determine the efficacy of DMPFC-rTMS for TRD under sham-controlled conditions. Methods: 120 TRD patients were randomized to receive 30 twice-daily sessions of either active highfrequency, active low-frequency, or sham DMPFC-rTMS using a novel bent active/sham double-cone coil. Placebo stimulation also involved the use of surface electrodes placed above the eyebrows. The 17-item Hamilton Rating Scale for Depression served as the primary outcome measure. Results: Although there was a significant main effect of treatment across all arms, active DMPFC-rTMS was not superior to sham. Both participants and assessors were unable to accuracy determine whether patients received active or placebo stimulation. However, technicians’ treatment arm guesses were significantly above chance. Conclusion: DMPFC rTMS did not result in improvement of depressive symptoms greater than sham stimulation. We cannot rule out that the sham apparatus may also have elicited an antidepressant effect via electrical trigeminal stimulation; future DMPFC-rTMS trials are therefore warranted. © 2019 Elsevier Inc. All rights reserved.
To the Editor: Treatment-resistant major depressive disorder (TRD) is associated with high rates of economic and personal burden [1]. Conventional rTMS for TRD employs left high-frequency or right lowfrequency dorsolateral prefrontal cortex (DLPFC), with response and remission rates between 50-55% and 30e35%, respectively, for the most recent generation of clinical trials [2]. One novel rTMS target for TRD is the dorsomedial prefrontal cortex (DMPFC) [3]. To date, a single double-blind sham-controlled trial of medial prefrontal rTMS for TRD has been published [4]. In that study, Kreuzer and colleagues reported a significant treatment groupby-time interaction on the primary clinical measure of their study, post hoc comparisons revealed that both active mPFC-rTMS and DLPFC-rTMS were not superior to sham rTMS. Despite this finding, open-label studies have found that roughly half of patients respond and one third of patients remit following DMPFC-rTMS; these rates are comparable to recent randomized controlled trials of DLPFCrTMS [2,3].
To improve clinical outcomes, rTMS protocols that theoretically elicit different physiological responses to the same brain region could be compared both for clinical efficacy and for effects on neural activity; such comparisons could help to identify mechanisms of response and to optimize treatment parameters. Consequently, the aim of the current study is to determine the treatment efficacy of high- and low-frequency active DMPFC-rTMS versus sham stimulation. We hypothesized that active 20 Hz DMPFC-rTMS would be superior to that of sham rTMS and 1 Hz DMPFC-rTMS. A complete description of the methods is found in the Supplemental Materials. To summarize, patients enrolled in the study met standardized criteria for MDD, failed to response to at least one course of antidepressant medication or psychotherapy within the current episode; and had a 17-item Hamilton Rating Scale for Depression (HRSD) score of at least 18 at the time of their screening visit. All participants provided informed consent, and the study was approved by the University Health Network Research Ethics Board (ClinicalTrials.gov Identifier: NCT02702154). Eligible participants were randomized into one of two active treatment arms: 1 Hz DMPFC-rTMS or 20 Hz DMPFC-rTMS, or a
https://doi.org/10.1016/j.brs.2019.10.020 1935-861X/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
2
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
sham rTMS arm. Before the first session of rTMS, the motor threshold for each participant was visually determined using previously published methods [5]. rTMS was delivered using the MagPro R30 stimulator and a specially designed Active/Sham DB80 (MagVenture, Farum, Denmark) coil for all rTMS treatments, with one double-cone coil in contact with the scalp for active treatment, and the opposite coil for sham stimulation. Surface electrodes connected to the stimulator were placed bilaterally above the eyebrows for all treatments. The 17-item HRSD [6] served as primary clinical outcome measures for the study, as in previously reported trials of DMPFC-rTMS [3,5]; the HRSD was administered pre-treatment, weekly (every 5 treatment days) throughout treatment, immediately posttreatment, and at 1-, 4-, and 12-weeks post-treatment. We used a mixed-effects model in SPSS (IBM Corp., Armonk, NY) to assess whether clinical improvement over the course of the study differed between the treatment arms, covarying for any clinical or demographic differences between treatment groups. 120 of the 143 MDD participants screened met the study’s eligibility requirements (78 female, mean age ¼ 39.44 ± 11.62), and 108 participants completed treatment (Table S1, Fig. S1). rTMS targeting the DMPFC was well-tolerated. A significant main effect of time was found (F(5,112) ¼ 27.60, p < 0.001), but there were no significant group-by-time interactions (F(10,113) ¼ 1.01, p ¼ 0.44) (Fig. 1). Neither clinical assessors nor patients were able to correctly guess treatment allocations better than chance (Assessor: c2 ¼ 0.02, df ¼ 1, p ¼ 0.88; Patient: c2 ¼ 0.42, df ¼ 1, p ¼ 0.52). However, technicians were able to determine who received active versus sham treatment significantly better than chance (c2 ¼ 23.69, df ¼ 1, p < 0.001). There are major methodological differences between the current study and previous trials of open-label and double-blind
DMPFC-rTMS that warrant further study of this treatment for TRD. First, unlike the original trial [4] and many [3,5] but not all [7,8] of our previous open-label studies, the current study employed 30 twice-daily 20 Hz rTMS sessions instead of 20e30 once-daily 10 Hz sessions. If the twice-daily stimulation did not achieve a twofold acceleration of effect in most patients, then the overall course length of 15 days may have been inadequate. However, a recent study of once-daily 10 Hz versus twice-daily 20 Hz open-label DMPFC-rTMS showed similar rates of improvement and response rates [8]. We also recently reported comparable response rates in an open-label case series of 20 Hz DMPFC-rTMS [7]. Another concern is whether the ‘sham’ stimulation electrodes, placed at regions above the eyebrows, might have inadvertently delivered therapeutic doses of transcranial electrical stimulation or trigeminal nerve (V1) stimulation. One sham-controlled trial [9] reported significant antidepressant effects of V1 stimulation. Although the V1 stimulatory parameters reported in these studies are unlike our sham stimulation, it is possible that these electrodes inadvertently induced an antidepressant effect in the sham arm via V1 stimulation. As sham design for TMS interventions is currently a major challenge in the field [10], future studies should consider alternative sham designs. To conclude, in this study our aim was to determine the clinical effects of DMPFC-rTMS in TRD under sham-controlled conditions. Contrary to our hypothesis, the clinical efficacy of 30 twice-daily sessions of excitatory DMPFC-rTMS was not superior to that of inhibitory rTMS or the sham procedure. Despite these findings, considerations such as sham apparatus design and the use of electrical stimulation to mimic the sensory effects of rTMS mean that DMPFC-rTMS for TRD warrants further study. Tested and validated under optimized sham-controlled conditions, DMPFC-rTMS
Fig. 1. Mean Hamilton Rating Scale for Depression from baseline to follow-up 2 (1 month follow-up) for the 20 Hz active, 1 Hz active, and sham DMPFC-rTMS treatment arms.
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
nonetheless has the potential to treat severe and treatmentnonresponsive psychiatric populations like TRD patients, who urgently need new, clinically effective interventions. Financial disclosures Dr. Dunlop was supported by the Canadian Institutes of Health Research Vanier Doctoral Fellowship and the Canadian Institutes of Health Research Banting Postdoctoral Fellowship. Ms. Schulze has received support from the Ontario Brain Institute via the Canadian Biomarker Initiative for Depression (CAN-BIND) and is also a recipient of the Ontario Mental Health Foundation (OMHF) studentship. Dr. Blumberger has received research grants from the Canadian Institutes of Health Research, 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; 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. Dr. Daskalakis has received research grants and equipment in-kind support for an investigator-initiated study from Brainsway and Magventure. Dr. Kennedy has received funding from Allergan, Brain Canada, Bristol-Meyers Squibb, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Medscape, Ontario Brain Institute, Otsuka, Pfizer, Servier, St. Jude Medical, Sunovion. Dr. Giacobbe has received research support from the CIHR and NIH; he has served as an unpaid consultant for St. Jude Medical, and he has served on advisory boards for Bristol-Myers Squibb and Janssen. Dr. Downar has received research support from the Canadian Institutes of Health Research, National Institutes of Health, Brain Canada, the National Institutes of Health, the Klarman Family Foundation, the Edgestone Foundation, and the Toronto General and Western Hospital Foundation, as well as travel stipends from Lundbeck and ANT Neuro, and in-kind equipment support for an investigator-initiated study from MagVenture. Declaration of competing interest Mr. Sheen, Mr. Fettes, Dr. Mansouri, Dr. Woodside and Dr. Feffer report no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.brs.2019.10.020.
References [1] Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med 2013;10:e1001547. https://doi.org/10.1371/journal.pmed.1001547. [2] Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet 2018;391:1683e92. https://doi.org/10.1016/ S0140-6736(18)30295-2. [3] Bakker N, Shahab S, Giacobbe P, Blumberger DM, Daskalakis ZJ, Kennedy SH, et al. rTMS of the dorsomedial prefrontal cortex for major depression: safety, tolerability, effectiveness, and outcome predictors for 10 Hz versus intermittent theta-burst stimulation. Brain Stimul 2015;8:208e15. https://doi.org/ 10.1016/j.brs.2014.11.002. [4] Kreuzer PM, Schecklmann M, Lehner A, Wetter TC, Poeppl TB, Rupprecht R, et al. The ACDC pilot trial: targeting the anterior cingulate by double cone coil rTMS for the treatment of depression. Brain Stimul 2015;8:240e6. https://doi.org/10.1016/j.brs.2014.11.014.
3
[5] Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP, et al. Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 2014;76:176e85. https://doi.org/ 10.1016/j.biopsych.2013.10.026. [6] Hamilton MC. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56e62. [7] Miron J-P, Feffer K, Cash RFH, Derakhshan D, Kim JMS, Fettes P, et al. Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series. Brain Stimul 2019. https://doi.org/10.1016/j.brs.2019.06.020. [8] Schulze L, Feffer K, Lozano C, Giacobbe P, Daskalakis ZJ, Blumberger DM, et al. 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. Brain Stimul 2018;11:327e36. https://doi.org/10.1016/ j.brs.2017.11.002. [9] Shiozawa P, da Silva ME, Netto GTM, Taiar I, Cordeiro Q. Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: a phase II, sham-controlled, randomized clinical trial. Epilepsy Behav 2015;44:23e6. https://doi.org/10.1016/j.yebeh.2014.12.024. [10] Duecker F, Sack AT. Rethinking the role of sham TMS. Front Psychol 2015;6: 210. https://doi.org/10.3389/fpsyg.2015.00210.
Katharine Dunlop* Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York City, United States Jack Sheen Institute of Medical Science, University of Toronto, Toronto, Canada Laura Schulze Institute of Medical Science, University of Toronto, Toronto, Canada Peter Fettes Institute of Medical Science, University of Toronto, Toronto, Canada Farrokh Mansouri Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada Kfir Feffer Lev-Hasharon Mental Health Center, Tzur-Moshe, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Daniel M. Blumberger Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Zafiris J. Daskalakis Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Sidney H. Kennedy Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada Krembil Research Institute, University Health Network, Toronto, Canada Peter Giacobbe Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, Canada
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
4
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
Krembil Research Institute, University Health Network, Toronto, Canada
Blake Woodside Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada Jonathan Downar Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada
*
Corresponding author. Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th Street, Box 240, New York, NY, 10021, USA. E-mail address: [email protected] (K. Dunlop). 18 October 2019 Available online xxx
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation
Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial a b s t r a c t Keywords: Repetitive transcranial magnetic stimulation (rTMS) Dorsomedial prefrontal cortex (DMPFC) Major depressive disorder (MDD)
Background: Dorsomedial prefrontal cortex (DMPFC) repetitive transcranial magnetic stimulation (rTMS) is a novel intervention for treatment-refractory depression (TRD). To date, many open-label case series and one randomized controlled trial of modest sample size have provided preliminary evidence that DMPFC-rTMS is an effective treatment for TRD. Here, we report the results of a large, doubleblinded, sham-controlled trial of DMPFC-rTMS for TRD. Objective: The primary aim of this study was to determine the efficacy of DMPFC-rTMS for TRD under sham-controlled conditions. Methods: 120 TRD patients were randomized to receive 30 twice-daily sessions of either active highfrequency, active low-frequency, or sham DMPFC-rTMS using a novel bent active/sham double-cone coil. Placebo stimulation also involved the use of surface electrodes placed above the eyebrows. The 17-item Hamilton Rating Scale for Depression served as the primary outcome measure. Results: Although there was a significant main effect of treatment across all arms, active DMPFC-rTMS was not superior to sham. Both participants and assessors were unable to accuracy determine whether patients received active or placebo stimulation. However, technicians’ treatment arm guesses were significantly above chance. Conclusion: DMPFC rTMS did not result in improvement of depressive symptoms greater than sham stimulation. We cannot rule out that the sham apparatus may also have elicited an antidepressant effect via electrical trigeminal stimulation; future DMPFC-rTMS trials are therefore warranted. © 2019 Elsevier Inc. All rights reserved.
To the Editor: Treatment-resistant major depressive disorder (TRD) is associated with high rates of economic and personal burden [1]. Conventional rTMS for TRD employs left high-frequency or right lowfrequency dorsolateral prefrontal cortex (DLPFC), with response and remission rates between 50-55% and 30e35%, respectively, for the most recent generation of clinical trials [2]. One novel rTMS target for TRD is the dorsomedial prefrontal cortex (DMPFC) [3]. To date, a single double-blind sham-controlled trial of medial prefrontal rTMS for TRD has been published [4]. In that study, Kreuzer and colleagues reported a significant treatment groupby-time interaction on the primary clinical measure of their study, post hoc comparisons revealed that both active mPFC-rTMS and DLPFC-rTMS were not superior to sham rTMS. Despite this finding, open-label studies have found that roughly half of patients respond and one third of patients remit following DMPFC-rTMS; these rates are comparable to recent randomized controlled trials of DLPFCrTMS [2,3].
To improve clinical outcomes, rTMS protocols that theoretically elicit different physiological responses to the same brain region could be compared both for clinical efficacy and for effects on neural activity; such comparisons could help to identify mechanisms of response and to optimize treatment parameters. Consequently, the aim of the current study is to determine the treatment efficacy of high- and low-frequency active DMPFC-rTMS versus sham stimulation. We hypothesized that active 20 Hz DMPFC-rTMS would be superior to that of sham rTMS and 1 Hz DMPFC-rTMS. A complete description of the methods is found in the Supplemental Materials. To summarize, patients enrolled in the study met standardized criteria for MDD, failed to response to at least one course of antidepressant medication or psychotherapy within the current episode; and had a 17-item Hamilton Rating Scale for Depression (HRSD) score of at least 18 at the time of their screening visit. All participants provided informed consent, and the study was approved by the University Health Network Research Ethics Board (ClinicalTrials.gov Identifier: NCT02702154). Eligible participants were randomized into one of two active treatment arms: 1 Hz DMPFC-rTMS or 20 Hz DMPFC-rTMS, or a
https://doi.org/10.1016/j.brs.2019.10.020 1935-861X/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
2
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
sham rTMS arm. Before the first session of rTMS, the motor threshold for each participant was visually determined using previously published methods [5]. rTMS was delivered using the MagPro R30 stimulator and a specially designed Active/Sham DB80 (MagVenture, Farum, Denmark) coil for all rTMS treatments, with one double-cone coil in contact with the scalp for active treatment, and the opposite coil for sham stimulation. Surface electrodes connected to the stimulator were placed bilaterally above the eyebrows for all treatments. The 17-item HRSD [6] served as primary clinical outcome measures for the study, as in previously reported trials of DMPFC-rTMS [3,5]; the HRSD was administered pre-treatment, weekly (every 5 treatment days) throughout treatment, immediately posttreatment, and at 1-, 4-, and 12-weeks post-treatment. We used a mixed-effects model in SPSS (IBM Corp., Armonk, NY) to assess whether clinical improvement over the course of the study differed between the treatment arms, covarying for any clinical or demographic differences between treatment groups. 120 of the 143 MDD participants screened met the study’s eligibility requirements (78 female, mean age ¼ 39.44 ± 11.62), and 108 participants completed treatment (Table S1, Fig. S1). rTMS targeting the DMPFC was well-tolerated. A significant main effect of time was found (F(5,112) ¼ 27.60, p < 0.001), but there were no significant group-by-time interactions (F(10,113) ¼ 1.01, p ¼ 0.44) (Fig. 1). Neither clinical assessors nor patients were able to correctly guess treatment allocations better than chance (Assessor: c2 ¼ 0.02, df ¼ 1, p ¼ 0.88; Patient: c2 ¼ 0.42, df ¼ 1, p ¼ 0.52). However, technicians were able to determine who received active versus sham treatment significantly better than chance (c2 ¼ 23.69, df ¼ 1, p < 0.001). There are major methodological differences between the current study and previous trials of open-label and double-blind
DMPFC-rTMS that warrant further study of this treatment for TRD. First, unlike the original trial [4] and many [3,5] but not all [7,8] of our previous open-label studies, the current study employed 30 twice-daily 20 Hz rTMS sessions instead of 20e30 once-daily 10 Hz sessions. If the twice-daily stimulation did not achieve a twofold acceleration of effect in most patients, then the overall course length of 15 days may have been inadequate. However, a recent study of once-daily 10 Hz versus twice-daily 20 Hz open-label DMPFC-rTMS showed similar rates of improvement and response rates [8]. We also recently reported comparable response rates in an open-label case series of 20 Hz DMPFC-rTMS [7]. Another concern is whether the ‘sham’ stimulation electrodes, placed at regions above the eyebrows, might have inadvertently delivered therapeutic doses of transcranial electrical stimulation or trigeminal nerve (V1) stimulation. One sham-controlled trial [9] reported significant antidepressant effects of V1 stimulation. Although the V1 stimulatory parameters reported in these studies are unlike our sham stimulation, it is possible that these electrodes inadvertently induced an antidepressant effect in the sham arm via V1 stimulation. As sham design for TMS interventions is currently a major challenge in the field [10], future studies should consider alternative sham designs. To conclude, in this study our aim was to determine the clinical effects of DMPFC-rTMS in TRD under sham-controlled conditions. Contrary to our hypothesis, the clinical efficacy of 30 twice-daily sessions of excitatory DMPFC-rTMS was not superior to that of inhibitory rTMS or the sham procedure. Despite these findings, considerations such as sham apparatus design and the use of electrical stimulation to mimic the sensory effects of rTMS mean that DMPFC-rTMS for TRD warrants further study. Tested and validated under optimized sham-controlled conditions, DMPFC-rTMS
Fig. 1. Mean Hamilton Rating Scale for Depression from baseline to follow-up 2 (1 month follow-up) for the 20 Hz active, 1 Hz active, and sham DMPFC-rTMS treatment arms.
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
nonetheless has the potential to treat severe and treatmentnonresponsive psychiatric populations like TRD patients, who urgently need new, clinically effective interventions. Financial disclosures Dr. Dunlop was supported by the Canadian Institutes of Health Research Vanier Doctoral Fellowship and the Canadian Institutes of Health Research Banting Postdoctoral Fellowship. Ms. Schulze has received support from the Ontario Brain Institute via the Canadian Biomarker Initiative for Depression (CAN-BIND) and is also a recipient of the Ontario Mental Health Foundation (OMHF) studentship. Dr. Blumberger has received research grants from the Canadian Institutes of Health Research, 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; 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. Dr. Daskalakis has received research grants and equipment in-kind support for an investigator-initiated study from Brainsway and Magventure. Dr. Kennedy has received funding from Allergan, Brain Canada, Bristol-Meyers Squibb, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Medscape, Ontario Brain Institute, Otsuka, Pfizer, Servier, St. Jude Medical, Sunovion. Dr. Giacobbe has received research support from the CIHR and NIH; he has served as an unpaid consultant for St. Jude Medical, and he has served on advisory boards for Bristol-Myers Squibb and Janssen. Dr. Downar has received research support from the Canadian Institutes of Health Research, National Institutes of Health, Brain Canada, the National Institutes of Health, the Klarman Family Foundation, the Edgestone Foundation, and the Toronto General and Western Hospital Foundation, as well as travel stipends from Lundbeck and ANT Neuro, and in-kind equipment support for an investigator-initiated study from MagVenture. Declaration of competing interest Mr. Sheen, Mr. Fettes, Dr. Mansouri, Dr. Woodside and Dr. Feffer report no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.brs.2019.10.020.
References [1] Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med 2013;10:e1001547. https://doi.org/10.1371/journal.pmed.1001547. [2] Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet 2018;391:1683e92. https://doi.org/10.1016/ S0140-6736(18)30295-2. [3] Bakker N, Shahab S, Giacobbe P, Blumberger DM, Daskalakis ZJ, Kennedy SH, et al. rTMS of the dorsomedial prefrontal cortex for major depression: safety, tolerability, effectiveness, and outcome predictors for 10 Hz versus intermittent theta-burst stimulation. Brain Stimul 2015;8:208e15. https://doi.org/ 10.1016/j.brs.2014.11.002. [4] Kreuzer PM, Schecklmann M, Lehner A, Wetter TC, Poeppl TB, Rupprecht R, et al. The ACDC pilot trial: targeting the anterior cingulate by double cone coil rTMS for the treatment of depression. Brain Stimul 2015;8:240e6. https://doi.org/10.1016/j.brs.2014.11.014.
3
[5] Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP, et al. Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 2014;76:176e85. https://doi.org/ 10.1016/j.biopsych.2013.10.026. [6] Hamilton MC. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56e62. [7] Miron J-P, Feffer K, Cash RFH, Derakhshan D, Kim JMS, Fettes P, et al. Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series. Brain Stimul 2019. https://doi.org/10.1016/j.brs.2019.06.020. [8] Schulze L, Feffer K, Lozano C, Giacobbe P, Daskalakis ZJ, Blumberger DM, et al. 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. Brain Stimul 2018;11:327e36. https://doi.org/10.1016/ j.brs.2017.11.002. [9] Shiozawa P, da Silva ME, Netto GTM, Taiar I, Cordeiro Q. Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: a phase II, sham-controlled, randomized clinical trial. Epilepsy Behav 2015;44:23e6. https://doi.org/10.1016/j.yebeh.2014.12.024. [10] Duecker F, Sack AT. Rethinking the role of sham TMS. Front Psychol 2015;6: 210. https://doi.org/10.3389/fpsyg.2015.00210.
Katharine Dunlop* Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York City, United States Jack Sheen Institute of Medical Science, University of Toronto, Toronto, Canada Laura Schulze Institute of Medical Science, University of Toronto, Toronto, Canada Peter Fettes Institute of Medical Science, University of Toronto, Toronto, Canada Farrokh Mansouri Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada Kfir Feffer Lev-Hasharon Mental Health Center, Tzur-Moshe, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Daniel M. Blumberger Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Zafiris J. Daskalakis Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Sidney H. Kennedy Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada Krembil Research Institute, University Health Network, Toronto, Canada Peter Giacobbe Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, Canada
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020
4
K. Dunlop et al. / Brain Stimulation xxx (xxxx) xxx
Krembil Research Institute, University Health Network, Toronto, Canada
Blake Woodside Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada Jonathan Downar Institute of Medical Science, University of Toronto, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Department of Psychiatry, University Health Network, Toronto, Canada
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Corresponding author. Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th Street, Box 240, New York, NY, 10021, USA. E-mail address: [email protected] (K. Dunlop). 18 October 2019 Available online xxx
Please cite this article as: Dunlop K et al., Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.10.020