rTMS Therapy and the dangers of flawed guideline development. An open letter to the RANZCP

For 20 years I have seen resistance to the development and uptake of repetitive Transcranial Magnetic Stimulation (rTMS) treatment in the Australian psychiatric community but truly felt we past this with the development of overwhelming evidence of its efficacy, especially when this was endorsed by the independent Australian Government Medicare Services Advisory Committee (MSAC) in their recommendations in regards to public funding of TMS in Australia. Unfortunately this seems to just have been wishful thinking.

Following the publication of a flawed Mood Disorders clinical practice guidelines (CPG) [1] under the auspice of the Royal Australian and New Zealand College of Psychiatry (RANZCP) in the Australian and New Zealand Journal of Psychiatry in January (see box), the authors of the original CPG have published an editorial addressing the way in which rTMS was presented in the original CPG [2].

This editorial is quite an extraordinary document and the fact that the CPG authors chose to follow up their own CPG with a ‘justification’ of how rTMS is presented in the CPG immediately after the publication of original document is also unusual, if not a little bizarre.

Firstly and most critically, if the original CPG had been developed in a methodologically rigorous and sound manner, there would be no need for, or any reason, to have to publish a justification for the decisions made in the CPG development process. As indicated by the Australian Government National Health and Medical Research Council (NHMRC), “Recommendations made in guidelines should be informed by well-conducted systematic reviews” (NHMRC., 2019). Unfortunately there was no process of systematic review adopted in the development of the college CPG leaving space for considerable personal opinion and selective referencing that requires the sort of justification the authors have now entered into.

The arguments in the justification are, however, unfortunately quite flawed and only really serve to draw attention to the major inadequacies that are present in the original CPG document itself. Even a cursory reading of the CPG (unless you have a long time it is hard to read the CPG in any more than a cursory way as it stretches for more than 70,000 words, many of which provide little practical advice on how to manage patients with mood disorders) will show that the authors have taken a stance against the clinical use of rTMS treatment in a manner which is completely at odds with that adopted in other international guidelines. This stance is also directly at odds with previous documents published by the college including the 2015 Mood Disorders CPG [3], the college position statement (PS) [4] and professional practice guidelines (PPG) [5] in regards to the use of rTMS therapy. The recommendations in the CPG are also inconsistent with the recommendations made by the independent Australian Government Medicare Services Advisory Committee (MSAC) in their recommendations in regards to public funding of TMS in Australia.

Of note, the college PPG and PS were developed by the college Section for ECT and Neurostimulation: the group within the college representing individuals with expertise in forms of therapy such as rTMS treatment. The section was given 14 days to review the 70,000 plus word Mood Disorders CPG document and almost all of the recommendations of the section were then completely disregarded. As such, the statement in the CPG that it involved “revisions in light of feedback from key college committees” should be considered sceptically.

It is also of considerable concern that “consensus-based recommendations” (CBRs) in the CPG were made in regards to rTMS treatment (and presumably in other areas of therapy) without including meaningful representation from the experts within the section or more broadly within the college. In my mind this certainly casts major doubts on the quality and accuracy of CBRs made within the guidelines.

If one was developing clinical recommendations that were significantly at odds with those seen in other professional documents including a previous CPG, recommendations of other professional bodies overseas and the college section, I would have thought that it would be imperative to make sure that these recommendations were as clearly justified by an up-to-date review and synthesis of the literature as would be possible. Unfortunately, this was not the case. There is no evidence that the guidelines were informed “by well-conducted systematic reviews”. In fact, the literature quoted in the section addressing the evidence pertaining to the use of rTMS in the treatment of depression was in no way up-to-date or comprehensive. A number of substantive recent meta-analysis, network meta-analysis and umbrella reviews addressing the evidence supporting rTMS therapy in depression have been published. However, the authors of the CPG chose to substantially rely on a 2016 Health Quality Ontario analysis (Health Quality, 2016) even though this has been more recently succeeded by more favourable review from the same group published in February 2019, well within the time frame of the revision of this CPG (Sehatzadeh et al., 2019).

In their recent editorial, the authors of the CPG attempt to justify their positioning of rTMS treatment through constructing a series of strawman  arguments which really are of little relevance. They somewhat irrelevantly postulate that that the use of rTMS has been proposed based on its mechanism of action:

“Given that rTMS is being promoted as a treatment for depression largely on the basis of its tolerability and novel mechanism of action rather than its efficacy a much deeper and clearer understanding of its effects is needed.…”.

They provide no support for this rather idiosyncratic notion and instead choose to ignore the 50+ clinical trials, 12 or more meta analyses etc. that have convinced regulatory authorities, and increasingly funders around the world of its value (as well as increasingly its cost effectiveness). The college’s own successful submission to the MSAC committee seeking public funding for rTMS therapy in no way relied on notions of novel mechanism of action, in fact these weren’t mentioned at all. A much deeper understanding of the effects, especially the clinical effects, of rTMS treatment for depression is actually available, it just wasn’t explored by the authors of the CPG and this editorial.

The authors also proposed that it is problematic that TMS has been evaluated in patients with treatment resistant depression (TRD) because there are problems with the concept of TRD itself:

“But treatment-resistant depression (TRD) is both inadequately and variably defined and this has meant there is great heterogeneity in the published data as regards the parameters used for stimulation, the clinical populations studied, and the outcomes of studies; and because of this the evidence supporting its efficacy is limited.”

I might be struggling a little bit cognitively but I fail to see the connection between the fact that rTMS is being evaluated in patients with TRD and that there is heterogeneity in stimulation parameters or even the outcome of studies. This has nothing to do with the evidence supporting efficacy being “limited”: as clearly stated above there is substantive evidence of efficacy for rTMS, in fact dramatically greater efficacy than for the vast majority of things that were recommended wholeheartedly in the CPG. In addition, the authors have no hesitance recommending other treatments for TRD and even contradict themselves by suggesting rTMS should be used in even more treatment resistant patients.

The authors then go on to state:

“Indeed, only rTMS applied to specific parts of the prefrontal cortex and at particular frequencies, holds some possibility of benefit, and even then only if administered to depressed patients in an acute phase of a medication-resistant episode of illness.”

Are they proposing that we should not use fluoxetine because it is not beneficial if rubbed on the skin? Or that we should not use lithium because it is not effective at any possible dose? It is actually reassuring that there is specificity between the target of treatment and clinical response and that an important stimulation variable such as frequency actually matters.

The fact that rTMS treatment works during the “acute phase of illness” also does not seem to be a problem. That the vast majority of research has focused on demonstrating the acute benefits of rTMS is obvious and makes perfect sense. Patients in the acute phase of depression desperately need access to better treatments. Certainly those who have failed to respond to more than 2 medications deserve access to better options than those proposed by the CPG authors: relatively endless trials of antidepressants and ‘augmentation’ even though we know that the outcomes of doing this are terrible. In fact the one substantive study to explore this found that less than 5% of patients having failed to respond to the first 2 medications were well in 12 months after further medication trials [6]). Many would agree that we require further studies exploring the use of rTMS as a maintenance treatment but we already have more studies of this nature than of a number of things unquestionably recommended in the guidelines; again the authors just don’t seem to have explored this literature at all.

These twisted arguments leave the authors of this CPG and editorial at the same flawed place. They conclude that rTMS should only be provided to patients who have had multiple courses of antidepressant medication.

“Before considering rTMS, patients should have failed to respond to a reasonable number of adequate trials of pharmacotherapy and psychological treatment Choices and adequate trials of Alternatives to treat depression. Pharmacotherapy Choices should ideally include antidepressants from putatively different classes (e.g. SSRIs, SNRIs, TCAs and MAOIs) and, where appropriate, each antidepressant should be suitably optimised through use of therapeutic dosing (e.g. increasing dose) and augmentation.”

This is provided in the CPG as a consensus based recommendation. It may well be the consensus of the authors but as described above, should not in any way be considered a consensus recommendations of those who truly understand literature supporting the use of rTMS treatment in depression. It is also worth making very clear here that this is not an evidence-based recommendation. The 2015 college CPG [7] made two clear evidence-based recommendation that are still is 100% valid in 2021:

“rTMS is an effective therapy that may be considered when patients have failed one or more trials of medication.

Patients with non-psychotic depression may be treated with rTMS once they have failed one or more trials of standard antidepressant medications and psychological therapies.”

These conclusions are unequivocal and evidenced based. For reasons that were not justified these were excluded by the authors from the current CPG.

It is important to repeat that the evidence supporting the use of rTMS therapy clearly supports these statements as reflected in clinical approvals around the world which have universally been for patients who have failed one or two antidepressant medication trials. There is no evidence supporting the statement that patients should have more extensive treatment from the medication classes listed above and including augmentation which typically involves medications with highly problematic side-effects such as obesity, diabetes, irreversible thyroid and renal failure. In fact anyone with even a relatively cursory understanding of the rTMS literature would be aware of studies indicating that the efficacy of rTMS is typically higher in those with lower levels of treatment resistance (Lisanby et al., 2009).

This would all be academic if these guidelines did not have clinical importance. rTMS is a relatively new therapy and as such groups like the RANZCP have an obligation to produce accurate and unbiased documents to inform its use. Unfortunately, the 2021 college depression CPG, as well as the editorial written in support of this, failed to provide a balanced, scientifically informed viewpoint. rTMS has not been addressed in a manner that is equivalent to that adopted in the review of other treatments, including those produced by the pharmaceutical industry.

There was a clear failure of evidence synthesis, consultation and consensus formation in the process of the development of these guidelines that was unnecessary and has resulted in the production of a highly flawed document. The fact that the authors chose to immediately write an editorial defending their position as it relates to one specific treatment, and within this continued to fail to address the scientific literature, is of serious concern.

The RANZCP should take responsibility and not allow this CPG to stand in its current form. The college has a responsibility to disseminate accurate information about treatments for mental health conditions and has failed in its responsibility in supporting the publication of this CPG. I call on the college to:

1.     Urgently review the processes undertaken to commission and review this CPG and to pause the production of any other CPGs in development until this has been completed

2.     Withdraw the Mood Disorders CPG until it can be redeveloped using the appropriate evidence based standards as defined by the NHMRC.

You can sign / endorse a letter expressing these concerns to the college here:

References

[1] Malhi GS, Bell E, Bassett D, et al. (2021) The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 55: 7-117.

[2] Malhi GS, Bell E, Murray G, et al. (2021) The positioning of rTMS. Aust N Z J Psychiatry 55: 125-128.

[3] https://www.ranzcp.org/files/resources/college_statements/clinician/cpg/mood-disorders-cpg.aspx

[4] https://www.ranzcp.org/news-policy/policy-and-advocacy/position-statements/repetitive-transcranial-magnetic-stimulation

[5] https://www.ranzcp.org/files/resources/college_statements/practice_guidelines/ppg16-administration-of-repetitive-transcranial-ma.aspx

[6] Sackeim HA. (2016) Acute Continuation and Maintenance Treatment of Major Depressive Episodes With Transcranial Magnetic Stimulation. Brain Stimul 9: 313-319.

[7] https://www.ranzcp.org/files/resources/college_statements/clinician/cpg/mood-disorders-cpg.aspx