Treatment‐resistant depression: where to find hope?

McIntyre et al's paper ¹ is not just another literature review on the topic of treatment‐resistant depression (TRD). It puts everyone in agreement and offers a concrete basis for a constructive reflection on the subject. More than that, it invites us to approach TRD in all its facets, the most complex but also those still unsuspected.

Since the 1970s, the scientific literature on TRD has abounded with proposals on how to define this condition ² . In the early days, extraordinarily complex definitions were proposed, all very elaborated and clever, but impractical or even impossible to apply in the clinic.

McIntyre et al provide a comprehensive picture of how we currently define TRD and emphasize that the picture remains blurry, as it is loaded with multiple elements resulting from too many angles of view. Beside the pragmatic definition proposed by regulatory authorities both in the US and in Europe, clinicians and researchers have nourished the picture extensively.

In general, the vast majority of attempts to define TRD describe the concept through the lens of treatment failures, i.e. the number and type of antidepressants that have not been effective in treating a depressive episode. Although this approach is fair and pragmatic, it must be said that it does not lead to a complete understanding of the problem. Some definitions have gone a step further and propose to include other parameters that are not directly related to treatment. This is the case, for example, of the Maudsley Staging Model, which attempts to define the degree of resistance by the severity and duration of the depressive episode, in addition to treatments that have not yielded results ³ . These measurable variables certainly have an impact on treatment resistance. Including these further data in the equation that defines TRD is certainly very helpful.

But, what if we were actually on the wrong track? TRD may be just an indication that different elements should be addressed. Elements that are not necessarily the target of antidepressants. No doubt that substantial results may be obtained by juggling with different antidepressants and how to use them in TRD. McIntyre et al's paper exhaustively reviews the different “tactics” that can be adopted. But it is clear that extending the antidepressant trial, or switching or combining antidepressants, are tactics which too often show their limits. As if with antidepressants we only targeted the visible, symptomatic component, while there are further upstream, more fundamental dimensions that cause resistance to treatment.

Some evidence in this respect comes from the fact that the use of substances other than antidepressants shows better results in TRD. As summarized in the paper, using second‐generation antipsychotics or ketamine/esketamine in combination with an antidepressant is amongst the most efficient strategies in TRD. Preliminary evidence also suggests that psilocybin, combined with psychotherapy, may offer rapid and possibly sustained symptom relief in adults with TRD. So, treatments which target dimensions other than the depressive symptomatology can significantly improve the insufficient results of antidepressants. It could be that these treatments act on neurophysiological or psychological dimensions upstream of depression, which may have a significant role in the lack of response to antidepressants. For example, an insufficient neural plasticity could be a basic factor in TRD, on which ketamine/esketamine or psylocibin may act. Moreover, at least six references in the paper are related to the link between childhood trauma and TRD. This can be seen as another example of a key fundamental dimension producing treatment resistance which could be targeted by approaches to TRD. A patient‐centric framework describing persons with multiple antidepressant failures, which focuses on causal, perpetuating and treatment factors ⁴ , may be needed.

All these considerations may also be a prompt to consider treatment resistance in the light of a transdiagnostic approach. It could be that factors such as childhood trauma, its negative impact on brain plasticity, and the disturbances that it generates in the circuits of fear and emotion management, are transdiagnostic elements involved in resistance to treatments in general.

In the section dedicated to therapeutic strategies, the authors also address the controversy over the switch within or across antidepressant classes in TRD. Actually, the evidence supporting the use of antidepressants from two different classes is weak. Papakostas et al ⁵ published the first meta‐analysis of data comparing switching strategies for depressed patients who failed to respond to a selective serotonin reuptake inhibitor (SSRI), i.e., switch to a second SSRI or a different antidepressant class. Results suggested only a marginal benefit of switching from one antidepressant class to another on remission rates. However, not all antidepressant classes were considered: only venlafaxine, mirtazapine and bupropion were included in the meta‐analysis. Thereafter, several reports have shown no advantage in switching to a different class of antidepressants ⁶ , ⁷ , ⁸ , ⁹ .

In conclusion, in the management of TRD, hope may lie in a vision that takes into account more fundamental elements than the mere depressive symptomatology. Antidepressants are of some use, but could not target these deeper elements. Depressive symptomatology may be only the last component activated by a multitude of upstream factors that should be the subject of more attention and research.