Daniel M. Blumberger, MD, MSc; Jerome J. Maller, MSc, PhD; Lauren Thomson, BSc; Benoit H. Mulsant, MD, MSc; Tarek K. Rajji, MD; Missy Maher, MEd; Patrick E. Brown, PhD; Jonathan Downar, MD, PhD; Fidel Vila-Rodriguez, MD; Paul B. Fitzgerald, MBBS, MPM, PhD; Zafiris J. Daskalakis, MD, PhD
Background: Several factors may mitigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) over sham rTMS in patients with treatment-resistant depression (TRD). These factors include unilateral stimulation (i.e., treatment of only the left dorsolateral prefrontal cortex [DLPFC]), suboptimal methods of targeting the DLPFC and insufficient stimulation intensity (based on coil-to-cortex distance).
Methods: We recruited patients with TRD between the ages of 18 and 85 years from a university hospital, and participants were randomized to receive sequential bilateral rTMS (600 pulses at 1 Hz followed by 1500 pulses at 10 Hz), unilateral high-frequency left (HFL)-rTMS (2100 pulses at 10 Hz) or sham rTMS for 3 or 6 weeks depending on treatment response. Stimulation was targeted with MRI localization over the junction of the middle and anterior thirds of the middle frontal gyrus, using 120% of the coil-to-cortex adjusted motor threshold. Our primary outcome of interest was the remission rate.
Results: A total of 121 patients participated in this study. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the HFL-rTMS group was intermediate and did not differ statistically from the rate in the 2 other groups. There were no significant differences in reduction of depression scores among the 3 groups.
Limitations: The number of pulses used per session in the unilateral group was somewhat lower in our trial than in more recent trials, and the sham condition did not involve active stimulation.
Conclusion: Our findings suggest that sequential bilateral rTMS is superior to sham rTMS; however, adjusting for coil-to-cortex distance did not yield enhanced efficacy rates.
Submitted Aug. 2, 2015; Revised Dec. 17, 2015; Revised Jan. 7, 2016; Accepted Jan. 12, 2016; Early-released June 7, 2016
Affiliations: From the Temerty Centre for Therapeutic Brain Intervention, and Campbell Family Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Blumberger, Thomson, Mulsant, Rajji, Maher, Daskalakis); the Monash Alfred Psychiatry research centre, The Alfred and Monash University Central Clinical School, Melbourne, Australia (Maller, Fitzgerald); Cancer Care Ontario and the Dalla Lana School of Public Health, University of Toronto, Toronto, Ont., Canada (Brown); the Toronto Western Hospital, University Health Network, Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Downar); and the Non-Invasive Neurostimulation Therapies laboratory, Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada (Vila-Rodriguez).
Competing interests: This work was funded by a Grant from the Ontario Mental Health Foundation (OMHF). D. Blumberger receives research support from the Canadian Institutes of Health Research (CIHR), Brain Canada, National Institutes of Health (NIH), Temerty Family through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Family Research Institute. He receives nonsalary operating funds and in-kind equipment support from Brainsway Ltd. for an investigator-initiated study. He is the site principal investigator for several sponsor-initiated clinical trials from Brainsway Ltd. He receives in-kind equipment support from Tonika/Magventure for an investigator-initiated study. B. Mulsant receives research support from CIHR, NIH, Brain Canada, the CAMH Foundation, Bristol-Myers Squibb (medications for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial). He owns stocks of General Electric (less than $5,000). Within the past five years, he has also received some travel support from Roche. T. Rajji receives research support from Brain Canada, the Brain and Behavior Research Foundation, the Canadian Foundation for Innovation, CIHR, the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation, NIH, and the W. Garfield Weston Foundation. J. Downar has received research support from CIHR, NIH, the Klarman Family Foundation, the Buchan Family Foundation, and the Toronto General and Western Hospital Foundation. He has also received a travel stipend from Lundbeck and from ANT Neuro, and in-kind equipment support for an investigator-initiated study from Tonika/Magventure. P. Fitzgerald is supported by an NHMRC Practitioner Fellowship (606907). He has received equipment for research from MagVenture A/S, Medtronic Ltd, Cervel Neurotech and Brainsway Ltd and funding for research from Cervel Neurotech. Z. Daskalakis has received external funding through Brainsway Ltd and a travel allowance through Pfizer and Merck. He has also received speaker funding through Sepracor Inc and AstraZeneca and has served on the advisory board for Hoffmann-La Roche Limited. He has received funding from OMHF, CIHR, the Brain and Behaviour Research Foundation and the Temerty Family and Grant Family and through the CAMH Foundation and the Campbell Institute. No other competing interests declared.
Contributors: D. Blumberger, B. Mulsant, T. Rajji, P. Brown and Z. Daskalakis designed the study. D. Blumberger, T. Rajji, M. Maher and Z. Daskalakis acquired the data, which D. Blumberger, J. Maller, L. Thomson, B. Mulsant, T. Rajji, P. Brown, J. Downar, F. Vila-Rodriguez, P. Fitzgerald and Z. Daskalakis analyzed. D. Blumberger, J. Maller, L. Thomson, T. Rajji, M. Maher and Z. Daskalakis wrote the article, which all authors reviewed and approved for publication.
Correspondence to: D.M. Blumberger or Z.J. Daskalakis, Centre for Addiction and Mental Health, University of Toronto, 1001 Queen St. West, Unit 4, First Floor, Toronto, ON M6J 1H4; email@example.com or firstname.lastname@example.org