The role of low-frequency repetitive transcranial magnetic stimulation in major depression: A call to increase the evidence base

Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD), with superior tolerability over medication [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for Mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (366) Google Scholar]. Unfortunately, its widespread adoption has been impeded by high operational costs, decreasing accessibility. These issues arise in part from the current protocols being favored, namely high-frequency (HF) rTMS, using figure-of-eight (Fo8) coils and targeting the left dorsolateral prefrontal cortex (L-DLPFC), and Deep TMS (using the H1 coil). The most recent rTMS guidelines considers them both to have the highest evidence, with level A ratings of "definite efficacy" [[2]Lefaucheur J.-P. Aleman A. Baeken C. Benninger D.H. Brunelin J. Lazzaro V.D. et al.Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018).Clin Neurophysiol. 2020; https://doi.org/10.1016/j.clinph.2019.11.002Crossref Scopus (787) Google Scholar]. An alternative that has now been studied for over 2 decades is low-frequency (LF) rTMS, usually 1 Hz right DLPFC (R-DLPFC) stimulation. Several RCTs have already demonstrated the superiority of R-DLPFC LF-rTMS over sham in MDD, and its efficacy has been confirmed in multiple meta-analyses. An oft-cited meta-analysis from 2012 (8 RCTs, 263 patients) suggested superior response (38.2% vs 15.1%) and remission rates (34.6% vs. 9.7%) vs. sham (p = 0.007 and p < 0.0001, RR 2.14, 95% CI = 1.02–4.47), with a number needed to treat (NNT) of 5 [[3]Berlim M.T. Eynde FV den Daskalakis Z.J. 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.Neuropsychopharmacology. 2012; 38: 543-551https://doi.org/10.1038/npp.2012.237Crossref PubMed Scopus (194) Google Scholar]. Higher number of pulses (>1200) was associated with higher response rates, and there were no differences in dropout rates between both groups. Superiority over sham of R-DLPFC LF-rTMS (OR 2.37, 95% CI = 1.52–3.68) was also confirmed in the most recent and largest meta-analysis on rTMS (81 RCTs, 4233 patients) [[4]Brunoni A.R. Chaimani A. Moffa A.H. Razza L.B. Gattaz W.F. Daskalakis Z.J. et al.Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes.Jama Psychiat. 2017; 74 (143–10)https://doi.org/10.1001/jamapsychiatry.2016.3644Crossref Scopus (294) Google Scholar]. Despite these encouraging results, the sham-controlled R-DLPFC LF-rTMS RCTs have been small N, single-center trials. The issue of blinding in rTMS has also often been contentious, and even though recent trials have successfully used surface electrodes placed above the eyebrows, this was not the case of the aforementioned LF rTMS RCTs. Blinding integrity was also not assessed. Given all of this, the most recently published rTMS guidelines [[2]Lefaucheur J.-P. Aleman A. Baeken C. Benninger D.H. Brunelin J. Lazzaro V.D. et al.Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018).Clin Neurophysiol. 2020; https://doi.org/10.1016/j.clinph.2019.11.002Crossref Scopus (787) Google Scholar] gave R-DLPFC LF-rTMS a rating of "probable antidepressant efficacy" (Level B). Conversely, the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines from 2016 gave R-DLPFC LF-rTMS level I evidence and ranked it as first line equally with L-DLPFC HF-rTMS, considering them equally efficacious [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for Mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (366) Google Scholar]. The most recent and largest meta-analysis (12 RCTs, 361 patients) confirmed this observation, showing similar response (OR 1.08, 95% CI = 0.88–1.34, p = 0.50) and remission rates (OR 1.29, 95% CI = 0.54–3.10, p = 0.56) [[5]Cao X. Deng C. Su X. Guo Y. Response and remission rates following high-frequency vs. Low-frequency repetitive transcranial magnetic stimulation (rTMS) over right DLPFC for treating major depressive disorder (MDD): a meta-analysis of randomized, double-blind trials.Front Psychiatr. 2018; 9: 1106-1107https://doi.org/10.3389/fpsyt.2018.00413Crossref Scopus (60) Google Scholar]. Unfortunately, most of the RCTs done on the subject were also of small N (largest 74), thus bringing once again the issue of lack of power and type-II error. Nevertheless, a recent and large (n = 300) four-arm RCT, not included in this meta-analysis (2 R-DLPFC LF-rTMS arms and 2 L-DLPFC HF-rTMS arms, 150 in each group), also concluded that both protocols had similar efficacy [[6]Fitzgerald P.B. Hoy K.E. Reynolds J. Singh A. Gunewardene R. Slack C. et al.A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression.Brain Stimul. 2019; https://doi.org/10.1016/j.brs.2019.09.001Abstract Full Text Full Text PDF Scopus (34) Google Scholar]. Beyond the issue of efficacy, LF-rTMS offers several advantages over the other FDA-approved protocols. There indeed is evidence that LF-rTMS causes less pain and has a higher safety profile - even in epilepsy patients - who show reductions of seizure frequency [7Loo C.K. McFarquhar T.F. Mitchell P.B. A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression.Int J Neuropsychopharmacol. 2008; 11: 131-147https://doi.org/10.1017/s1461145707007717Crossref PubMed Scopus (0) Google Scholar, 8Sun W. Mao W. Meng X. Wang D. Qiao L. Tao W. et al.Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.Epilepsia. 2012; 53: 1782-1789https://doi.org/10.1111/j.1528-1167.2012.03626.xCrossref PubMed Scopus (127) Google Scholar, 9Kaur M. Michael J.A. Fitzgibbon B.M. Hoy K.E. Fitzgerald P.B. Low-frequency rTMS is better tolerated than high-frequency rTMS in healthy people: empirical evidence from a single session study.J Psychiatr Res. 2019; 113: 79-82https://doi.org/10.1016/j.jpsychires.2019.03.015Crossref PubMed Scopus (15) Google Scholar]. More importantly though, the greatest potential of LF-rTMS may lie in the potential to improve accessibility, tolerability, safety, and equipment costs associated with the technique, which should spark the interest of clinics and healthcare policymakers. Indeed, 1 Hz rTMS only requires very basic stimulators, which could be much more affordable than usual setups required for HF and Deep TMS. Our group also recently published a case series on easy-of-use non-cooled non-focal parabolic coils [[10]Miron J.-P. Voetterl H. Mansouri F. Blumberger D.M. Daskalakis Z.J. Downar J. A case series of a novel 1 Hz right-sided dorsolateral prefrontal cortex rTMS protocol in major depression.Brain Stimul. 2019; https://doi.org/10.1016/j.brs.2019.11.006Abstract Full Text Full Text PDF Scopus (5) Google Scholar]. These could be an affordable alternative to cooled coils, while also offering a solution to targeting issues given their non-focality. Additionally, given its safety and simplicity of administration on large coils, 1 Hz rTMS could potentially offer a pathway toward the development of devices suitable for home use. Home-based 1 Hz rTMS would address the two most significant downsides of rTMS over medication: the need for patients to come to clinics for treatment, and the cost of the treatment sessions. A device capable of delivering basic 1 Hz stimulation currently costs in the range of $15,000 – amortized over a 5-year use period, this would equate to under $9 a day, which is comparable to many antidepressant medication regimens. Home rTMS would also facilitate maintenance treatments, a still unresolved issue in rTMS [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for Mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (366) Google Scholar]. Finally, treatment at home decreases patient contact, social distancing now being a necessary, albeit unfortunate new reality of the COVID-19 "pandemic era" [[11]Caulfield K.A. George M.S. Treating the mental Health effects of COVID-19: the need for at-home neurotherapeutics is now.Brain Stimul. 2020; https://doi.org/10.1016/j.brs.2020.04.005Abstract Full Text Full Text PDF Scopus (20) Google Scholar]. Before this can become a reality, we need to clearly establish the efficacy of 1 Hz rTMS. Indeed, critics will point out, and rightly so, that the aforementioned evidence is insufficient, given the lower quality of the evidence compared to HF or rTMS. We thus believe that properly powered RCTs with adequate blinding are therefore needed, which could even take the form of an eventual home-based trial. As a community of healthcare providers and scientists, we believe that we should always strive for innovations allowing maximal accessibility to novel treatments on behalf of our patients. We believe that a form of 'accessibility-optimized' LF-rTMS protocol could eventually offer comparable convenience and cost to medications, while preserving the efficacy and tolerability of the technique. This would help make rTMS more accessible to the population worldwide, creating a pathway toward meaningful reductions in the overall prevalence of depression and anxiety in the general population, beyond what has been achieved via conventional therapies to date. The authors declare no financial interests relative to this work. JPM reports research grants from the Brain & Behavior Research Foundation NARSAD Young Investigator Award and salary support for his graduate studies from the Branch Out Neurological Foundation. JS and FM do not report any conflict of interest. DMB receives research support from CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. He is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. FVR reports grants from Canadian Institutes of Health Research, grants from Brain Canada, grants from Vancouver Coastal Health Research Institute, grants from Michael Smith Foundation for Health Research, personal fees from Janssen Pharmaceuticals, in-kind equipment for investigator-initiated research from Magventure. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work was supported by the Ontario Mental Health Foundation (OMHF), the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH) and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. JD reports research grants from CIHR, the National Institute of Mental Health, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Weston Foundation, the Klarman Family Foundation, the Arrell Family Foundation, and the Buchan Family Foundation, travel stipends from Lundbeck and ANT Neuro, in-kind equipment support for investigator-initiated trials from MagVenture, and is an advisor for BrainCheck, TMS Neuro Solutions, and Restorative Brain Clinics.

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