Re-positioning rTMS: From ECT magic,to magical thinking!

The quaint letter by George and Pridmore (2021) provides a titillating modicum of neurostimulation history, but only a glimpse of research in the form of a small pilot study was conducted by one of the authors, which involved a total of 6 participants. The letter flits through a number of major issues in quick succession. First, it attempts to justify the use of transcranial magnetic stimulation (TMS) in comparison with electroconvulsive therapy (ECT) on the basis of it being more localised and therefore less likely to cause cognitive side effects. However, at the same time, the authors note that when initially conceived as a treatment for depression, repetitive transcranial magnetic stimulation (rTMS) ‘hoped to harness some ECT magic’. The separation of clinical benefit and cognitive compromise was presumed to be possible with more targeted stimulation, as reported in a 1996 Lancet paper by Pascual-Leone et al. (1996) who noted a reduction of mood symptoms in 11 of 17 severely depressed patients (with psychosis), without side effects, in a sham-controlled focal rTMS study. On the basis of this, they predicted that ‘rTMS of the left dorsolateral prefrontal cortex might become a safe, non-convulsive alternative to electroconvulsive treatment in depression’, and in so doing sparked worldwide research in the field.

Interestingly, the authors then compare rTMS with psychological treatments and pharmacotherapy, and justify the latter, on the basis of expense – noting that rTMS is expensive because of set-up costs and the need for clinical supervision. However, notably, the authors avoid mentioning comparative efficacy (e.g. TMS vs antidepressants or psychological therapy) and there is no mention whatsoever of depressive phenotypes in which rTMS might have differential effects. Instead, they suggest that rTMS was reserved for treatment-resistant patients because of the risk of side effects (that were at that time unknown), and therefore, rTMS was positioned initially in the management of depression because of a pragmatic concern for both cost and tolerability. But when considering current modern-day practice, the latter is quickly negated because of being ‘unrealised’, and importantly, there is no mention of the significant cost of TMS in clinical settings.

Finally, in their penultimate paragraph, although the authors set out with the statement that there ‘was no extravagant expectation of replacing ECT’, they then compare TMS with ECT, asserting that it ‘has a better balance of efficacy and acceptability’ while conceding that ECT is ‘more efficacious’.

Remarkably, in all of this, the authors provide no evidence for the efficacy of rTMS. Given their near 30-year association with TMS, surely some robust research studies should have been undertaken. This would enable them to mount a criticism based on data and unequivocal findings rather than snippets of history coupled with assertions based on preliminary studies with very small numbers. Disappointingly, there is also no discussion of the cost involved in administering TMS, nor indeed a discussion of the kind of patients for whom it is best suited. In other words, which patients with depressive disorders are most likely to benefit from rTMS. Furthermore, when and how should rTMS be administered in order to optimise benefit? On these key clinical questions, the authors are remarkably restrained.

In contrast, the mood disorders clinical practice guidelines (Malhi et al., 2021a) carefully discuss the research that has been conducted regarding the use of rTMS in the treatment of depression and this has been further detailed in recent viewpoints (Malhi et al., 2021b, 2021c). The sum conclusion of these deliberations is that rTMS has not accumulated sufficient evidence to warrant its inclusion in the routine management of depression. And that, in comparison with rTMS, ECT is the preferred treatment for severe depression or depression with psychotic symptoms. Furthermore, there is insufficient evidence to recommend rTMS to patients who have failed to respond to ECT.

When questioning our positioning of rTMS in the management of depression, the kinds of questions we have posed and the related clinical considerations are what we would have expected experts in the field to address. Instead, somewhat unimaginatively, on the basis of past practice and the requirements of insurers, they stick to their standard positioning of rTMS as ‘after two failed treatment attempts and before ECT’. This leap from poor evidence and little proof, to specific and unwavering recommendations, is the only aspect of TMS that strikes us as magical.