Revisiting the effectiveness of repetitive transcranial magnetic stimulation treatment in depression,again

Abstract

Following on from the publication of the Royal Australian and New Zealand Journal of Psychiatry Mood Disorder Clinical Practice Guidelines (2020) and criticisms of how these aberrantly addressed repetitive transcranial magnetic stimulation treatment of depression, questions have continued to be raised in the journal about this treatment by a small group of authors, whose views we contend do not reflect the broad acceptance of this treatment nationally and internationally. In fact, the evidence supporting the use of repetitive transcranial magnetic stimulation treatment in depression is unambiguous and substantial, consisting of an extensive series of clinical trials supported by multiple meta-analyses, network meta-analysis and umbrella reviews. Importantly, the use of repetitive transcranial magnetic stimulation treatment in depression has also been subject to a series of health economic analyses. These indicate that repetitive transcranial magnetic stimulation is a cost-effective therapy and have been used in some jurisdictions, including Australia, in support of public funding. An argument has been made that offering repetitive transcranial magnetic stimulation treatment may delay potentially effective pharmacotherapy. In fact, there is considerably greater danger of the opposite happening. Repetitive transcranial magnetic stimulation is as, if not more effective, than antidepressant medication after two unsuccessful medication trials and should be a consideration for all patients under these circumstances where available. There is no meaningful ongoing debate about the use of repetitive transcranial magnetic stimulation treatment in depression – it is a safe, effective and cost-effective treatment.

In a recent issue of the journal, Malhi et al. (2021a) restate claims made by the first author about repetitive transcranial magnetic stimulation (rTMS) treatment for depression that the ‘evidence for the efficacy of this intervention is still very much in its infancy’ and that ‘the jury is very much out as to whether there is a meaningful signal with rTMS delivery in the treatment of depression’. The authors support these claims only by references to the same lead author’s previous publications and with no systematic review of the evidence. As has been presented recently in this journal (Fitzgerald et al., 2021a) and described extensively elsewhere (e.g. Brunoni et al., 2017; Papadimitropoulou et al., 2017; Razza et al., 2020), these statements are inaccurate (see Table 1). In fact, there already exists a substantive evidence base supporting the use of rTMS in the treatment of depression that extends from multisite clinical trials to multiple meta-analyses, network meta-analyses, umbrella reviews and large-scale real-world treatment outcome data (Fitzgerald et al., 2021a). Scientific support for the efficacy and cost-effectiveness of rTMS for depression is by no means in ‘its infancy’: in fact it is consistent with that required to support the clinical use of a new treatment and is underwritten by a wealth of data exploring its neurobiological mechanisms (Luan et al., 2020) and real-world outcomes (Sackeim et al., 2020).

Table 1.

rTMS-related myths and corresponding evidence-supported statements.

rTMS in depression: Myth debunker
Myth	Fact	Level of evidence (National Health and Medical Research Council [NHMRC], 2009)/Note	References
Evidence for the effectiveness of rTMS is still very much in its infancy	rTMS is a well-established effective treatment in depression	Level I	Fitzgerald et al., 2021a; Razza et al., 2020; Mutz et al., 2018; Ontario Health (Quality), 2021; Papadimitropoulou et al., 2017; Brunoni et al., 2017; Li et al., 2021
rTMS is recommended for tolerability more than evidence	Although rTMS is highly tolerable, its effectiveness is the primary reason for prescribing it	Level I for both effectiveness and tolerability	Fitzgerald et al., 2021a; Razza et al., 2020; Mutz et al., 2018; Ontario Health (Quality), 2021; Papadimitropoulou et al., 2017; Brunoni et al., 2017; Li et al., 2021; Valiengo et al., 2021; Zis et al., 2020
RANZCP Mood Disorder Guidelines (2020) have evidence-based recommendations for rTMS	The RANZCP Mood Disorder Guidelines (2020) provided only ‘Consensus-Based Recommendations’ which were developed excluding the views of the relevant college expert body	Clear Level 1 evidence-based guidelines were provided in the previous RANZCP Mood Disorders Guidelines (2015)	Malhi et al. (2015)
rTMS is not cost-effective treatment	rTMS is a cost-effective treatment	Level I–II evidence rTMS has been found to be cost-effective by independent health technology assessment authorities	See Table 2

Malhi et al. (2021b) also cite the recently published RANZCP clinical practice guidelines for mood disorders. However, the way in which these guidelines addressed rTMS therapy has been criticised in regard to both the content and process of their development (Fitzgerald et al., 2021b). Most critically, the guidelines omitted the substantive level 1 evidence that supports the efficacy of rTMS (and which was included in a previous version of the college guidelines; Malhi et al., 2015). Instead, the 2020 guideline included ‘Consensus-Based Recommendations’ which were based on erroneous arguments and developed with a critical lack of due process (Fitzgerald et al., 2021b). Specifically, rTMS was addressed with an out-of-date and selective, not systematic, review. Second, the ‘consensus’ and consultation process were wholly inadequate. There was no formal consensus process involving individuals, especially experts in the field, outside of the authorship group. The guideline authors provided the draft guideline to the committee of the RANZCP’s Section for ECT and Neurostimulation but then ignored the opinion of the committee, who represent the relevant specialists in the field, which was that the guideline’s appraisal of the evidence for rTMS was substantially inaccurate and inadequate (Fitzgerald et al., 2021b).

The strong evidence supporting the efficacy of rTMS render arguments such as ‘When the efficacy of rTMS is questioned a common response is that because rTMS is highly tolerable there is no harm trying it’ meaningless. In fact, the true ‘hidden costs’ derive from denying patients timely access to rTMS, not when rTMS is offered instead of medication. Given that the evidence points to rTMS being more effective than continued pharmacological treatments once patients have failed several antidepressant trials (Fitzgerald et al., 2021a; Papadimitropoulou et al., 2017), then continuing further trials of various medication strategies (which in real-world practice can be protracted over years) instead of offering rTMS therapy constitutes withholding effective treatment and introducing the risk of harms associated with chronic or worsening depression. Repeated unsuccessful trials of medication are much more likely to lead to adverse consequences than a trial of rTMS. An initial trial of rTMS to establish efficacy is time-limited, does not require medication titration/withholding/washout and has about a 50% chance of achieving depression treatment response (Sackeim et al., 2020). Denying or delaying rTMS treatment can have real-world consequences. Clinically, we have seen patients denied access to rTMS who reported adverse outcomes of treatment denial or delay.

Given that Malhi et al. refer to ‘hidden costs’, we should consider the cost-effectiveness of rTMS in depression. Consistent with the data supporting its efficacy, the cost-effectiveness of rTMS is endorsed in the literature, both in academic studies and those conducted by funding bodies and groups that inform government policy (Nguyen and Gordon, 2015; Teng et al., 2020; Ontario Health (Quality), 2021; Voigt et al., 2017, and see Table 2). For example, an analysis by researchers from Griffith University concluded that rTMS was a ‘dominant/cost-effective alternative for patients with treatment resistant depressive disorder’ and produced higher quality-adjusted life years (QALY) than antidepressant medications at less cost (Nguyen and Gordon, 2015). The most recent analysis, by the independent Ontario Health Technology Assessment group, found that a course of rTMS followed by electroconvulsive therapy (ECT) was significantly more cost-effective than ECT alone, and rTMS was cost-effective compared to antidepressant medication at the frequently used standard of US$50,000 per QALY (Ontario Health (Quality), 2021). Another analysis that specifically evaluated the cost-effectiveness of rTMS if used earlier in the course of treatment and over a patient’s lifetime supported the use of rTMS after a single failed antidepressant trial (Voigt et al., 2017). This analysis also found that rTMS was significantly more cost-effective compared to repeat antidepressant medication trials, resulting in lower costs and better outcomes across a range of age groups. Across these analyses there is a clear indication that rTMS is cost-effective compared to antidepressant medication although there are less consistent findings when comparing rTMS to ECT.

Table 2.

Summary of cost-effectiveness studies examining use of rTMS in depression.

Authors	Methodology and perspective used	Results
Voigt et al. (2017)	Lifetime Markov Stimulation modelling Direct costs vs medication costs and QALYs Perspective: Societal	rTMS dominant to antidepressants in all ages over life of the patients with major depressive disorder
Fitzgibbon et al. (2020)	Markov model Cost utility analysis of lifetime costs and benefits to society of rTMS and ECT as first-line treatments for Treatment-Resistant Depression (TRD) Perspective: Societal	rTMS is a cost-effective first line treatment option for TRD when utilising a lifetime horizon
Zhao et al. (2018)	State Transition Markov model (decision analytic model) Cost and benefit of rTMS compared with ECT over 1 year in patients with TRD Perspective: Societal	rTMS has lower costs and QALYs over 1 year in patients with TRD Cost-effectiveness of rTMS was attenuated when ECT was used in the outpatient setting
Health Quality Ontario (Ontario Health (Quality), 2021)	Cost utility analysis with a 3-year horizon from a public payer perspective Perspective: Health care payer	rTMS followed by ECT in rTMS non-responders was less expensive and more effective than rTMS alone. rTMS was cost-effective compared to pharmacotherapy alone at a willingness-to-pay amount of $50,000 per quality-adjusted life-year (QALY)
Nguyen and Gordon (2015)	3-year Markov microsimulation model Costs and QALYs of rTMS with mix of antidepressant medications in patients with TRD Perspective: Health system	rTMS was a dominant cost-effective alternative for patients with TRD QALY gained with rTMS were higher than those gained with antidepressant medications
Vallejo-Torres et al. (2015)	Base care economic model (Markov) Cost-effectiveness analysis comparing ECT alone, rTMS alone and rTMS followed by ECT when rTMS fails Perspective: Spanish health service	ECT alone was less costly and more effective than rTMS alone
Ghiasvand et al. (2016)	Decision tree model Cost-effectiveness ratio of rTMS compared with ECT in patients with major depression in a 7 months horizon Perspective: Health system	ECT is more cost-effective than TMS. If prevalence of major depressive disorder declines to below 5% or the costs of rTMS decrease (rTMS provided by public sector), then the rTMS becomes more cost-effective compared with ECT

QALY: quality-adjusted life year.

Seeing that these responses and their supporting evidence have been detailed and discussed in recent publications, we also question the scholarly quality of Malhi et al. (2021a) and the value of its publication. It provides no primary data or new analysis. Rather, it revisits assertions that have been rebutted and negated. Clearly inaccurate statements such as the efficacy of rTMS being ‘very much in its infancy’ and that ‘the jury is very much out’ just create doubt and confusion, do not advance meaningful debate and risk damaging the scholarly reputation of the College journal. The journal’s readership and contributors expect its contents to be evidence-based and meet the highest standards of scholarly rigour.

The efficacy of rTMS has been consistently established by independent bodies most recently in Australia by the Medical Services Advisory Committee of the Department of Health. As with all therapies in clinical psychiatry, continued research is required to enhance the efficacy, efficiency and clinical utility of rTMS. We continue to engage in this research and welcome the publication of new, original research and primary evidence that nuances the clinical role and biological mechanisms of rTMS.