Stimulating dangerous argument?

In our first foray into this subject (Malhi et al., 2019), we tentatively raised the question of whether we need to know more about the practical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. From the two responses furnished by Professors Fitzgerald (2019) and Pridmore (2019), it would appear our wariness was valid, and that indeed we should not only be posing such questions but, in fact, demanding answers. What is clear thus far is that the only answers to be had are based on meager evidence, and that support for any position one chooses to adopt, even those one may be opposed to, can be readily garnered. That is, all parties can draw on a case study, open label trial or single randomized controlled trial (RCT) to promote their arguments, but there is no preponderance of evidence to support a clear strategy. Questions regarding the use of rTMS that have no definitive answers as yet include whether rTMS should be used instead of electroconvulsive therapy (ECT), whether it is effective when administered after ECT, to what extent is it modified by anxiety or concomitant benzodiazepine use, what are the optimal treatment parameters for treating depression, and the most effective number of treatment sessions, and what level of improvement warrants further intervention. For all of these questions, the current evidence base is insufficient, although it is worth noting that in a separate recent article Pridmore states (Pridmore and Pridmore, 2019), ‘while ECT sometimes causes remission where TMS has failed, TMS rarely causes remission where ECT has failed’. What is perhaps of greater concern is that rTMS is being used in protracted treatment trials in patients for whom response appears to be least likely, as in our case study.

It is possible that our comments have been construed as a more general critique of rTMS, and have therefore attracted attempts to defend the technology as a whole. And so we would like to re-emphasize our key concern: namely, that there are many significant gaps in the evidence between demonstrating efficacy of rTMS as a therapy and informing clinical decision-making. Furthermore, and most worrying, is the fact that despite these shortcomings rTMS is being offered more widely and with mounting enthusiasm.

Pridmore (2019) claims benzodiazepine use is not a contraindication, but cites evidence that showed those taking benzodiazepines have a poorer response and has not provided any evidence that supports the contrary argument. Fitzgerald (2019) is more conciliatory and agrees, for instance, that further research is needed to address the key concern highlighted in our case study: ‘... there is a relatively sparse literature exploring what is a sufficiently long course of TMS therapy prior to a determination of non-response’. Of further concern, it is not clear whether these issues are being adequately explored, and the statements from Pridmore and Fitzgerald provide little reassurance that these clinical considerations are likely to be subjected to rigorous research.

Considering the responses carefully, we also want to add some further words of caution. In practice, managing patients who are suffering with treatment resistant depression is indeed difficult, to say the least. Part of this difficulty is that this group is extremely heterogeneous and thus studies of effective treatments are inevitably challenging and vary in their applicability to each individual. As a clinician, having to accept that one is at the end of the line and that the only treatment options remaining are experimental is humbling, as much as it is frustrating. It is all too easy in such circumstances to justify doing something—no matter what, after all, it is surely better than doing nothing? But really, this can be a very dangerous approach that can inadvertently lead to harm because, simply put, all treatments come at a price—whether it be side effects, financial burden, or an opportunity cost.

Of course, this does not mean that experimental treatment approaches should not be considered and trialed. However, we must make sure that all variables have been considered and the patient is fully aware of gaps in the evidence and the limitations of what is known—especially as applied to their particular case. For example, it is necessary to communicate clearly that the experimental nature of the trial means that it is unknown whether they themselves specifically will benefit, and also that there are costs, both tangible and indirect, of pursuing this treatment. In comparison to some other therapies used in the management of treatment resistant depression, rTMS seems to have fewer side-effects, and often this is taken to mean that a trial is relatively harmless and perhaps ‘worth a try’. However, time engaged in ineffective therapy is time the patient remains unwell and continues to suffer. It is also time that may have been better used trialing an alternative. Therefore, trials of rTMS should begin with accurate information as regards the treatment and likely outcomes, and should be limited in the first instance to 20 sessions, as guidelines suggest (Milev et al., 2016)—with ongoing reappraisal of the need for treatment. This allows for a new and potentially more effective course to be taken if little-to-no improvements are seen early in the course of treatment. Importantly, as with all cases of treatment-resistant depression, time and effort should be directed toward re-examining and reformulating the patient’s illness, with management maintaining a sensible step-wise approach.

Finally, it is also important to consider the hidden costs. Patients with treatment-resistant depression are vulnerable and understandably are often desperate for any glimmer of hope. It is our responsibility to ensure patients continue to trust the medical profession and do not ever feel exploited. The reputation of the profession is potentially at risk if we encourage our patients to try costly treatments that have little likelihood of working. To avoid losing integrity in the eyes of our patients, and indeed society as a whole, we must make certain that we always prescribe treatments that are ultimately in their best interests.