Letter to the Editor regarding ‘Five facts about rTMS?’

To the Editor

In a recent issue of the journal, Malhi and Bell (2022) present misleading claims about rTMS as ‘facts’ but provide no evidence for these other than references to their own opinion-based articles rather than reference to original research. No attempt has been made to address the considerable body of evidence presented in previous articles addressing these claims (e.g. Fitzgerald et al., 2021) or to provide a balanced or systematic review of the actual evidence. These claims and evidence-based rebuttals are presented in Table 1.

Table 1.

rTMS-related claims by Malhi and Bell (2022) and facts supported by systematic evidence.

Five claims by Malhi et al. a	Five evidence-supported facts about rTMS
Lacks comparative efficacy in the management of clinical depression.	rTMS treatment of depression is supported by an extensive series of clinical trials, meta-analyses and systematic reviews (e.g. Brunoni et al., 2017; Razza et al., 2020) and its comparative efficacy is supported by a substantive network meta-analysis (Papadimitropoulou et al., 2017).
Tolerability and safety have been over-emphasised and serious potential harms have been overlooked.	The use of rTMS is supported by 30 years of clinical trials demonstrating a substantial track record of safety and an absence of serious risk of harms. Excellent tolerability of rTMS is supported by meta-analysis summarising the results of over 90 clinical trials (Zis et al., 2020), a body of evidence exceeding that for any other treatment in psychiatry.
Claimed benefits are almost completely attributable to placebo and non-specific effects.	Efficacy of rTMS is robust and meaningfully in excess of benefits seen with placebo as reflected in the positive assessments of the efficacy of rTMS by independent assessment and funding agencies (e.g. Ontario, 2021).
It is not known what kind of depression is suited to rTMS. Note that treatment-resistant depression is not a diagnostic subtype.	rTMS is effective in patients with depression who have failed to respond to one or more antidepressant medications, a clearly defined group of patients (Ontario, 2021).
There is a startling paucity of basic neuroscience and animal studies investigating the effects of rTMS neural functioning.	The use of rTMS is supported by over 35 years of animal and human neuroscience studies providing a broad and deep understanding of its effects at a wide variety of explanatory levels (e.g. Luan et al., 2020).

a

References included in the original article (Malhi and Bell, 2022) have not been included here.

First, the comparative efficacy of rTMS has been documented in a network meta-analysis (notably published by authors from the pharmaceutical industry) which found that rTMS produced either the equal best or clearly best outcomes on response and remission rates after 4 and 6 weeks of treatment compared to all other interventions for treatment-resistant depression (TRD): clear evidence of ‘comparative efficacy’ (Papadimitropoulou et al., 2017). The overall efficacy of rTMS has been explored although in a more limited set of studies than the vast (over 50) randomised trials (see among other studies, Brunoni et al., 2017; Razza et al., 2020) which have confirmed that it is an effective intervention when compared to sham (Fitzgerald et al., 2021). These sham-controlled studies of rTMS in patients who have failed two or more medications show that active treatment results in superior outcomes to those reported at the equivalent third or fourth levels in the STAR*D trial. Compared to ECT, while some studies have demonstrated superior outcomes for ECT (usually when comparing unlimited numbers of unilateral and bilateral ECT to a fixed number of one form of rTMS, hardly a valid comparison), the majority have reported similar outcomes.

Second, the tolerability and safety of rTMS is well established. Malhi et al. raise alarmist concerns of ‘serious potential harms’ but can cite no evidence of the emergence of these in 35+ years since rTMS was first used. The most recent systematic review of tolerability was able to review the results from 93 trials and found remarkably low rates of adverse events and discontinuation rates that did not differ from those seen with sham stimulation (Zis et al., 2020). Clearly this is a very well-tolerated treatment which compares favourably with most treatments for psychiatric conditions, especially treatments such as atypical antipsychotics, lithium and ECT used in TRD.

Third, there is overwhelming evidence of antidepressant effects of rTMS greater than those attributable to placebo: this includes over 50 clinical trials, meta-analyses, systematic reviews, umbrella reviews and real-world studies clearly demonstrating efficacy, superiority to placebo and clinical utility (Fitzgerald et al., 2021).

Fourth, rTMS is effective in a pragmatically definable and clinically extremely important proportion of depressed individuals who have failed to respond to other treatments (i.e. in TRD). Whether this is actually a ‘subtype’ is not relevant to the clinical utility of this, or other treatments approved for clinical use based on these criteria.

Fifth, exploration of the basic neuroscience of rTMS has been undertaken since 1985 and includes extensive animal studies (Luan et al., 2020) as well as studies using human neuroscience tools such as EEG and neuroimaging (Aceves-Serrano et al., 2022) all of which can easily be identified with a search of the literature.

The five ‘facts’ proposed by Malhi et al. are clearly unsupported by meaningful evidence and misleading to readers.