rTMS for depression: The difficult transition from research to clinical practice

Abstract

The publication of the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of mood disorders was followed by a series of correspondences discussing the place of repetitive transcranial magnetic stimulation (rTMS) in the sequence care for the routine treatment of depression. The controversy has led to an intense debate about the positioning of this neuromodulation technique in the clinical armamentarium for depression in the Australian and New Zealand Journal of Psychiatry. The many arguments presented by the authors to defend their respective points of view can be summarised in two main key issues: (i) the interpretation of the level of evidence of rTMS for depression and (ii) the characterisation of patients who could benefit from this treatment. In this viewpoint, we discuss the difficult transition from research to clinical practice regarding the use of rTMS to treat depression.

The publication of the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of mood disorders (Malhi Gin et al., 2021a) was followed by a series of correspondences discussing the place of repetitive transcranial magnetic stimulation (rTMS) in the sequence care for the routine treatment of depression (Fitzgerald et al., 2021; Malhi Gin et al., 2021b, 2021c). The controversy has led to an intense debate about the positioning of this neuromodulation technique in the clinical armamentarium for depression in the Australian and New Zealand Journal of Psychiatry.

Transcranial magnetic stimulation (TMS) is a non-invasive method of brain stimulation first described by Barker et al. in 1985. This innovative technique has undoubtedly led to significant advances in the field of fundamental neurosciences, providing a unique tool to study causal brain/behaviour relationships (Valero-Cabré et al., 2017). However, progress in understanding the brain functions is not necessarily associated with advances in the treatment of brain diseases. It is this ‘transitional challenge’ that leads Malhi et al. and Fitzgerald et al. to drastically opposing views regarding the positioning of rTMS in the management of depression. The many arguments presented by the authors to defend their respective points of view can be summarized in two main key issues: (1) the interpretation of the level of evidence of rTMS for depression and (2) the characterisation of patients who could benefit from this treatment.

To defend the use of rTMS in clinical practice, Fitzgerald et al. (2021) cite several meta-analyses and network meta-analyses stating that they provide the highest level of evidence to demonstrate the efficacy of this technique. Indeed, meta-analyses have become so influential that they can shape guidelines and change clinical practice. We believe that this view needs to be broadly balanced. The production of meta-analyses has reached ‘epidemic proportions’ in recent years and discordant meta-analyses on the same topic have become a common recurring issue for diverse clinical questions (Palpacuer et al., 2019). In fact, meta-analyses can no longer be considered as indisputable gold standard but rather as specific methods with their advantages and disadvantages that are also logically induced by the bias and confounding factors found in primary studies (Esterhuizen and Thabane, 2016; Palpacuer et al., 2019). In this context, we have recently showed evidence of a spurious excess of statistically significant results in the rTMS literature for all the neuropsychiatric disorders including depression (Amad et al., 2019). Excess significance may result from numerous factors, especially in small and heterogeneous studies exploring the efficacy of rTMS in depression. These studies correspond to 50 small sample size randomized controlled trials (median number of subjects per study = 32.5, [interquartile range, 24–57.3]). Caution is therefore needed to interpret the results of meta-analyses before drawing any conclusion for clinical practice. The same level of scrutiny is required when interpreting the results of network meta-analyses that compare multiple treatments simultaneously in a single analysis by combining direct and indirect evidence. Indeed, one has to bear in mind that this method is still evolving and can yield very different results according to the inclusion criteria used (Palpacuer et al., 2019). In summary, blindly translating the results of meta-analyses into practical guidelines cannot be a valid approach for evidence-based medicine. The careful examination of primary studies is an essential step to establish the place of a therapeutic in clinical practice.

The fine-grained characterization of patients who may benefit from the technique is also a challenge that is currently far from being solved. Yet, this stage is essential to clearly position the use of rTMS in daily practice with patients suffering from depression. In their viewpoint, Fitzgerald et al. consider depression (or major depressive disorder) as a broad diagnostic category. This approach is reflected in the ‘Professional Practice Guidelines 16’ by the statement that rTMS is an appropriate treatment for both treatment-resistant (i.e. patients who have failed to respond to one or more antidepressant medication treatments, according to the authors definition) and non-treatment-resistant depression. We think that this totally undifferentiated perspective on which patients might benefit from rTMS is highly questionable in a time when significant efforts are being made to better characterize the clinical profiles of patients with depression and to disentangle the mechanisms of treatment resistance. On one hand, patients with depression can be described according to the severity of the disease (mild, moderate, severe), clinical features (e.g. catatonic, psychotic) and various underlying mechanisms (e.g. negative cognitive schema). On the other hand, treatment resistance can be associated with a myriad of different mechanisms (e.g. wrong diagnosis, inadequate treatment, pharmacogenetics) and simply considering a ‘failure to respond to one or more antidepressant’ does not reflect the complexity of this phenomenon.

In conclusion, the development of non-invasive neuromodulation techniques, of which rTMS is the current main tool, has been accompanied by many promises for the treatment of depression and other psychiatric disorders. The absence of significant adverse effects associated with the use of these methods is frequently emphasized as a reason for their widespread use. However, it is important to be particularly vigilant about the positioning of these tools in clinical practice guidelines and not to succumb to ‘neuroenchantment’ (a form fascination with brain science) (Ali et al., 2014). We are convinced that the vivid debate between Malhi et al. and Fitzegerald et al. should not be seen as a pro/con opposition but rather as an exciting opportunity to optimize research protocols and develop studies able to reliably determine the effect of rTMS in depression.