{"doi":"10.1016/j.brs.2020.06.013","title":"The role of low-frequency repetitive transcranial magnetic stimulation in major depression: A call to increase the evidence base","abstract":"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. 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