rTMS and treatment-resistant depression: The need to consider class action!

In the recent Federal budget, the Australian Government committed to funding repetitive transcranial magnetic stimulation (rTMS) using Medicare items from November 2021 to tackle ‘treatment-resistant’ depression (TRD). ¹ However, the threshold for this, namely ‘two different classes of antidepressants,’ is too low and unnecessarily rigid. Furthermore, many aspects for this indication are poorly defined and open to interpretation. To be eligible, patients must have received two courses of antidepressants and a course of psychological therapy, but despite these measures, patients remain unwell. This broad ‘indication’ is worrying given that rTMS remains an experimental therapy and both ‘TRD’ and what constitutes remaining unwell are poorly defined. Furthermore, the nature and extent of psychological therapy is not specified. However, of greater concern, and the focus of this article, is the arbitrary specification of two medication classes, which is not in keeping with the options and strategies available to treat depression successfully.

In recent articles, we have highlighted the gaps in the evidence and the limited efficacy of rTMS in the management of depression using this treatment modality. We have also drawn attention to the possibility that the majority of the effects of TMS are attributable to Placebo and Non-Specific Effects (PANSE) rather than the specific action of brain stimulation per se (Malhi and Bell, 2021).

Furthermore, we have shown that rTMS is at best an experimental intervention because it has yet to conclusively establish (1) efficacy as a treatment for depression (against placebo), (2) comparative efficacy (against other established treatments) and (3) identify a clinical phenotype for whom it is best suited. In other words, what kind of depression is likely to benefit from the intervention and when should it be considered; these studies are yet to be conducted.

Meanwhile, in clinical practice, we have argued that experimental treatments should only be considered once all recognised and well-established therapies have been given reasonable consideration and suitably trialled. We remain of the view that TRD and similar constructs, such as difficult to treat depression (DTD), set up a negative therapeutic relationship, are not clinically meaningful and should be supplanted by our channelling response paradigm. This offers a more positive and clinically relevant means of determining a treatment pathway for depression. However, if for pragmatic purposes a threshold of reasonable treatment strategies is needed, then this should be determined on the basis of evidence and logic.

Hence, in this brief article, we focus on what may be considered a reasonable threshold to trigger the consideration of an experimental strategy in the management of depression, such as TMS in particular, but also other treatments, for example, esketamine. Note, we have not examined the equally critical issue of gauging wellness, which because of its complexity requires sophisticated appraisal, but have chosen instead to focus initially on psychological interventions and pharmacotherapy.

When to consider experimental alternatives?

Psychological therapies

As per the Royal Australian and New Zealand College of Psychiatrists (RANZCP) guidelines (Malhi et al., 2021a), we suggest that from the outset, all depression must be managed using lifestyle measures and alongside these strategies a suitable, evidence-based psychological intervention should be instituted. Whether the latter has been effective or not should be determined by the psychologist administering therapy ensuring that an appropriate dose (number of sessions accompanied by the appropriate ingredients [fidelity to the model]) has been provided. As with pharmacological treatments, continuous monitoring of progress and response should occur to ensure that a full course of psychological therapy has been delivered to constitute a legitimate trial. If a patient has previously failed to complete a course of psychological therapy, it is important to establish the exact reasons why and which aspects of the therapy have not worked for this individual. Certain factors that may lead to an individual failing to complete a course such as a poor relationship with the clinician or an inability to complete homework should be addressed to ensure the treatment is delivered properly and comprehensively before moving on to other potential interventions.

Antidepressant medications

Either in conjunction with or following psychological interventions, medication can be considered if deemed appropriate. When considering medication for the treatment of depression, our guidelines nominate seven antidepressants (referred to as Choices) that represent the prototypical agents for different classes of antidepressants – based principally on their mechanisms of action (Malhi et al., 2021a). And although pharmacologically there is some overlap between the actions of the seven molecules, they are sufficiently different in their properties to be considered as separate therapeutic options. In practice, not all will be available in every circumstance, and in some cases, particular medications may not be well tolerated.

To determine when sufficient pharmacotherapeutic options have been explored, a heuristic approach is needed and ideally, as many classes of antidepressants as possible should be trialled. However, it is important to note that although the actions of the seven Choice antidepressants are distinct, the mechanisms of some molecules are more similar to others. Therefore, in practice, when reviewing what medications have already been trialled, it may be necessary to further group these agents into broader classes. For example, the selective serotonin reuptake inhibitors (SSRIs) form a well-recognised and established class that comprises six agents. ² However, given the similarity of action between the agents in this class and the ‘serotonin neuromodulator’ action of vortioxetine, the latter can perhaps be regarded broadly as a serotonergic agent. In contrast, agomelatine clearly has a very distinct mechanism of action – working primarily via melatonin and 5HT_2c receptors. The next set of Choice agents (venlafaxine, mirtazapine and bupropion) are generally regarded as more potent because of their broader recruitment of neurotransmission within the brain. Here, the dual-action reuptake inhibitors venlafaxine and bupropion, both act on noradrenaline but have preferential actions on serotonin and dopamine, respectively, and therefore can also be loosely grouped together as a class. In a similar vein, mirtazapine also has dual actions on both serotonergic and noradrenergic neurotransmitter systems, but because its receptor binding properties are different, and it modulates these systems in a different manner, it is generally regarded as having a separate action to that of venlafaxine and bupropion, and a distinct set of properties.

Thus, at this point, there are roughly four classes of antidepressants, all of which have proven efficacy and are reasonably tolerated. And in practice when treating depression, moving through these four classes should usually lead to remission and recovery, as shown in the STAR*D effectiveness study (Rush et al., 2006). However, in some cases, and especially where there are melancholic symptoms of depression or additional psychotic features, it may be useful to consider medications that are generally more efficacious, but usually less well tolerated. These include the tricyclic antidepressants (TCAs), but also the monoamine oxidase inhibitors. In this ‘group’, there are some anomalies in that some of the molecules are described on the basis of their molecular structure (e.g. TCAs), rather than their actions. In terms of their effects, TCAs can be regarded as ‘multiple-action antidepressants’ – as they impact both serotonin and noradrenaline increasing monoamine neurotransmission and also act on additional neurotransmitter systems such as histamine and acetylcholine. In contrast, the monoaminoxidase (MAO) inhibitors do what their name implies, and, because of the universal function of MAO in neurotransmission, they too have a very broad and effective action. However, their metabolic interactions and the need for dietary restrictions are limiting factors. Therefore, it seems reasonable to say that several classes of antidepressants can be logically trialled and many of these should be utilised, together with augmentation strategies, according to the principles outlined by the MiDAS paradigm (Malhi et al., 2021a).

As an example, a typical approach to the use of antidepressants might include an SSRI/vortioxetine or agomelatine (where this is available) to begin, followed by mirtazapine or a dual-action agent, and then a tricyclic antidepressant (all administered at an adequate dose for a sufficient time). Note, there is ample flexibility both in terms of choice and to some extent the order in which agents are prescribed. In this respect, there is likely to be considerable real-world variation in clinical practice because of patient preference and suitability. For example, in patients with more severe depression, a dual-action agent may be the agent that is initiated first, or indeed a tricyclic antidepressant, and in some cases electroconvulsive therapy (ECT) may be a suitable option from the outset. In this manner, a number of classes of agents can be trialled and a number of strategies and kinds of therapeutic interventions should be considered before embarking upon experimental strategies (see Figure 1).

Figure 1.

Schematic illustrating management strategies to be implemented before considering experimental treatments. This schematic shows that for the management of depression, a number of types of treatments should be trialled before considering experimental interventions such as rTMS. First, psychological treatments should be trialled, wherein the therapy should be evidence-based, delivered by a trained clinician and completed in full with genuine engagement (e.g. completion of set tasks/homework). Following on from psychological therapy, or in conjunction with it, antidepressant medications should be prescribed, with each trial employing the strategies of the MiDAS paradigm (Medication, increase Dose, Augment, Switch). Medications from several different classes should be trialled in this same manner, and at each juncture, before trialling each consecutive intervention, clinicians should Re-Evaluate Assigned Diagnosis (READ). Ideally, treatment should be tailored to the individual, and therefore the number and kinds of classes of antidepressants trialled can follow a number of pathways, as indicated by the solid and dashed lines. For example, an individual may trial 3 (ACE), 4 (ABDE) or even 5 (ABCDE) different classes of antidepressants. Once a sufficient number of medications from different classes have been suitably trialled, ECT can be considered, with optimised delivery in accordance with current guidelines (see Malhi et al., 2021a) – noting that depending on individual circumstances, ECT may need to be considered at any point in the treatment algorithm and may be the primary intervention in some cases such as psychotic depression. Finally, only once all established treatment avenues have been reasonably pursued should experimental treatments, such as rTMS or esketamine, be considered, but again only after thorough re-evaluation of the diagnosis has been undertaken.

Treatment-resistant depression

A key flaw with the eligibility criteria for rTMS is that it is reliant on the artificial construct of treatment-resistant depression (TRD). TRD has increasingly been identified as a redundant concept that should not play a significant role in the determination of treatment as it has little clinical utility or prognostic value. This is because TRD reflects a heterogeneous myriad of clinical, biological, psychological and social factors that contribute to non-response (Fava et al., 2020). And the term TRD does not take into account depressive episodes that persist due to ongoing psychosocial stressors (such as interpersonal violence or severe personality dysfunction) or lifestyle factors such as lack of exercise or alcohol consumption that maintain the depression. Triggering rTMS or potentially any other treatment for TRD is problematic because it prematurely impedes personalised therapeutic intervention (Fava et al., 2020; Malhi et al., 2021a), and importantly, the threshold for categorising treatment non-response will inevitably vary from individual to individual, and clinician to clinician, creating the likelihood of misapplication and the possibility of misuse. For instance, some clinicians may consider a patient to have TRD with little or no consideration of the contributing factors (see Box 1) and simply judge any previous treatment exposure as evidence of having failed treatment and regard this as sufficient reason for prescribing rTMS. Prematurely triggering costly experimental strategies under the presumption that they will somehow be more successful than well-established treatments could be regarded as irresponsible – especially as experimental treatments are often associated with considerable hidden costs (Malhi et al., 2021b).

Box 1.

Factors that contribute to non-response.

● Biological considerations such as individual predispositions, for example, personality, genetic and epigenetic factors; allostatic load and cumulative damage ● Clinical parameters such as treatment history, medical and psychiatric comorbidities; diagnostic reformulations, for example, switching from depression to hypomania/mania, or habituation effects ● Psychosocial factors, cognitive factors, attitudes towards treatment, trauma exposure or life events, persistent interpersonal violence, workplace bullying, personality dysfunction (disorder) ● All factors variably influence how each individual responds to their treatment at any given time

Thus, TRD is not a phenotype of depression and a rigid interpretation of this label and the premature institution of an experimental interventions such as rTMS is not without significant risks.

Conclusion

In practice, rTMS may produce clinical improvement, but this is usually transient and it is most likely to be a consequence of PANSE, which occurs because of intensive engagement (Malhi and Bell, 2021). Importantly, these effects are not sustained and do not address the underlying illness. There are significant hidden costs and potential harms associated with TMS (Malhi et al., 2021b), which are likely to be a problem given that TRD is poorly defined. Therefore, it will be critical to ensure that patients undergoing any form of stimulation therapy have suitably exhausted conventional routine effective treatments (as outlined above) and that they do in fact have a depressive illness. To this end, referrals for rTMS should only be made after an assessment by a psychiatrist to ensure that all reasonable alternatives have been adequately trialled. Furthermore, patients should be advised that TMS lacks a substantive evidence base, is largely an experimental intervention, the precise indications for which are yet to be determined, as are the optimal parameters for administration and that it is unlikely to be successful in the longer term.