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Published Online: 15 February 2019

Trajectories of Response to Dorsolateral Prefrontal rTMS in Major Depression: A THREE-D Study

Tyler S. Kaster, M.D., Jonathan Downar, M.D., Ph.D., Fidel Vila-Rodriguez, M.D., Ph.D., Kevin E. Thorpe, M.Math., Kfir Feffer, M.D., Yoshihiro Noda, M.D., Ph.D., Peter Giacobbe, M.D., Yuliya Knyahnytska, M.D., Ph.D., Sidney H. Kennedy, M.D., Ph.D., Raymond W. Lam, M.D., Zafiris J. Daskalakis, M.D., Ph.D., and Daniel M. Blumberger, M.D., M.Sc. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 176, Number 5
https://doi.org/10.1176/appi.ajp.2018.18091096
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Abstract

Objective:

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics.

Methods:

This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4–6 weeks (20–30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics.

Results:

Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology–Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory.

Conclusions:

Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 176 • Number 5 • May 01, 2019
Pages: 367 - 375
PubMed: 30764649

History

Received: 25 September 2018
Revision received: 18 November 2018
Accepted: 17 December 2018
Published online: 15 February 2019
Published in print: May 01, 2019

Keywords

  1. Mood Disorders-Unipolar
  2. Depressive Disorder, Treatment-Resistant
  3. Transcranial Magnetic Stimulation
  4. Treatment Outcome
  5. Longitudinal Studies, Clinical Trials

Authors

Affiliations

Tyler S. Kaster, M.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Jonathan Downar, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Fidel Vila-Rodriguez, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Kevin E. Thorpe, M.Math.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Kfir Feffer, M.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Yoshihiro Noda, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Peter Giacobbe, M.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Yuliya Knyahnytska, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Sidney H. Kennedy, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Raymond W. Lam, M.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Zafiris J. Daskalakis, M.D., Ph.D.
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Daniel M. Blumberger, M.D., M.Sc. [email protected]
The Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto (Kaster, Knyahnytska, Daskalakis, Blumberger); the Department of Psychiatry (Kaster, Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), the Institute of Medical Science (Downar, Giacobbe, Kennedy, Daskalakis, Blumberger), and the Dalla Lana School of Public Health (Thorpe), University of Toronto, Toronto; the MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto (Downar); the Krembil Research Institute, University Health Network, Toronto (Downar, Kennedy); the Department of Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez, Lam); the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver (Vila-Rodriguez); the Shalvata Mental Health Center, Hod-Hasharon, Israel, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv (Feffer); the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (Noda); the Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto (Giacobbe); and the Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto (Kennedy).
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Notes

Send correspondence to Dr. Blumberger ([email protected]).

Competing Interests

Dr. Downar has received research support from the Arrell Family Foundation, Brain Canada, the Buchan Family Foundation, the Canadian Biomarker Integration Network in Depression, the Canadian Institutes of Health Research (CIHR), the Edgestone Foundation, the Klarman Family Foundation, NIMH, and the Ontario Brain Institute; he has received travel stipends from Lundbeck and ANT Neuro; he has served as an adviser for BrainCheck, Restorative Brain Clinics, and TMS Neuro Solutions. Dr. Vila-Rodriguez has received research support from Brain Canada, CIHR, the Michael Smith Foundation for Health Research, and the Vancouver Coastal Health Research Institute, and he has participated on an advisory board for Janssen. Dr. Noda has received a Grant-in-Aid for Young Scientists (KAKENHI) and a research grant from the Japan Agency for Medical Research and Development; and he has received an investigator-initiated clinical study grant from Teijin Pharma Limited and research grants from the Daiichi Sankyo Scholarship Donation Program, the Health Science Center Foundation, the Japan Health Foundation, the Meiji Yasuda Mental Health Foundation, the Mitsui Life Social Welfare Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Senshin Medical Research Foundation, and the Takeda Science Foundation. 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. Kennedy has received research support or consulting or speaking honoraria from Abbott, Alkermes, Allergan, Brain Canada, Bristol-Myers Squibb, CIHR, Janssen, Lundbeck, the Lundbeck Institute, the Ontario Brain Institute, the Ontario Research Fund, Otsuka, Pfizer, Servier, St. Jude Medical, Sunovion, and Xian-Janssen. Dr. Lam has received research funds or honoraria for speaking, advising, or consulting from Akili, Allergan, Asia-Pacific Economic Cooperation, the BC Leading Edge Foundation, Brain Canada, CIHR, the Canadian Depression Research and Intervention Network, the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, the CME Institute, Hansoh, Janssen, Lundbeck, the Lundbeck Institute, Medscape, Mind Mental Health Technologies, Otsuka, Pfizer, St. Jude Medical, the University Health Network Foundation, and the VGH Foundation. Dr. Daskalakis has received research support and in-kind equipment support for an investigator-initiated study through Brainsway and MagVenture. Dr. Blumberger has received research support from Brain Canada, CIHR, NIH, the Weston Brain Institute, and the Temerty Family through the CAMH Foundation and the Campbell Research Institute; he has received research support and in-kind equipment support for an investigator-initiated study from Brainsway and is the site principal investigator for three sponsor-initiated studies for Brainsway; he has received medication supplies for an investigator-initiated trial from Indivior; and he has participated on an advisory board for Janssen. The other authors report no financial relationships with commercial interests.

Funding Information

Canadian Institutes for Health Research: MOP-136801

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