Switching antidepressants in patients with treatment-resistant depression

Introduction

Despite the availability of many therapeutic strategies, the optimal treatment of depression remains a major challenge. The overall effectiveness of antidepressants remains limited, and in almost 30%–50%, the response to treatment will be insufficient or absent ( ; ). The concept of treatment-resistant depression (TRD) is often used to characterize these complex situations where more than one antidepressant trial is needed to achieve response or remission ( ). This implies that in many cases it will be necessary to change the antidepressant, even if the choice of the first treatment was adequate based on the clinical picture. Given the high prevalence of major depression and the significant risk of poor or insufficient response to the first or second treatment step, any clinician involved in the treatment of depression, whether psychiatrist or general practitioner, will very often be confronted with patients with TRD. This reality is even more frequent for psychiatrists who practice in hospital care units dedicated to difficult-to-treat cases.

This issue raises several clinically important questions. When it is necessary to consider a change of treatment, how to achieve this change of treatment and especially what therapeutic choice after a first failure? The second-step strategy after nonresponse to an antidepressant remains a real clinical challenge. Although different strategies are recommended, it is difficult to predict their efficacy. The current lack of biological predictors of treatment response leaves the clinician to rely on some clinical factors that have been associated to TRD. Severity of the depressive episode, anxiety disorders comorbidity or high suicidal risk are among key clinical factors associated to lack of response to antidepressant therapy ( ; ; ).

At present, the choice of second step strategy is essentially based on the clinic and the prescriber’s experience. Recommended strategies include optimization (high-dose antidepressant therapy) ( ), augmentation (especially with lithium or second-generation antipsychotics) ( ; ), combining two antidepressants ( ), electroconvulsive therapy ( ), various psychotherapeutic approaches ( ), novel or experimental treatments ( ), and switching to a different antidepressant ( ). suggested the “SACO” mnemonic (Switching therapies, Augmentation, Combination and Optimization) to aid providers in choosing the next option in TRD. There are many reviews of the literature on these different strategies, but it remains difficult to have clear recommendations on which attitude to adopt as a second step. To our knowledge, there are no completely reliable clinical indications to guide the physician in the attitude to adopt.

Switching to a different antidepressant is a common strategy, mainly in the situation of complete nonresponse to the first antidepressant and in case of tolerability issues. The issue of switching antidepressant in TRD is fundamental and needs to be addressed from different perspectives. At first, this question is a basic element of the definition of the concept of TRD. It refers to the number of antidepressant trials required before considering resistance to treatment. In parallel, the second step antidepressant choice is also qualitatively important and raises the question of considering a change in antidepressant class. For example, it may make sense to switch to an SNRI after failure to an SSRI. For many clinicians, there will be a preconception that they need to switch to an antidepressant with a different mechanism of action in the hope of achieving a better result. This issue has been the subject of much debate. A metaanalysis concluded that there is no significant benefit to switch across class ( ).

In this chapter, we propose to address these issues from a clinical perspective, focusing on key elements of the switching strategy in TRD: implication in the definition of TRD, how to implement the treatment switch and choice of second step treatment.

Switching antidepressant and TRD definition

Is switching part of the TRD concept?

How is the question of switching between antidepressants crucial in defining the concept of TRD? For decades, since the 1970s, the scientific literature on the subject has abounded with proposals to define TRD. In the early days, extraordinarily complex definitions were proposed, all very elaborated and clever but impractical and often impossible to apply in the clinic. This first wave of definitions of TRD was also of little use for possible clinical trials aimed at evaluating the efficacy of a treatment or therapeutic strategy in TRD. It was a time, moreover, when there were no studies of this type and no recognition of a treatment in this indication. The basic principle of this first generation of definitions was to consider a depression as resistant to treatment only if the patient had been treated by multiple drugs or biological therapies, with the imperative to have received what was considered at the time as the most powerful treatments. At that time tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), lithium, and electro convulsive therapy (ECT) were among the treatments to be incorporated in any TRD definition but all of them in different sequences and with various durations based on empirical assumptions. The main thing was therefore to consider TRD only if the depressive episode had benefited from these treatments.

Switching in staging models of TRD

Subsequently, more pragmatic proposals appeared, it was the era of staging models to better characterize TRD. These models are clinically extremely useful and have significantly contributed to a better understanding of the different stages of resistance to treatment in depression ( ). They give more space to the notion of “switching” regardless of the bias on relative effectiveness among the options used. Although particularly useful in the clinic, these models are however little or not used in clinical trials. They have therefore never contributed to demonstrating the efficacy of a treatment or a therapeutic strategy in TRD. Moreover, they are not considered by the regulatory authorities in charge of recognizing a specific indication in TRD, neither in Europe nor in the United States.

Switching antidepressant and clinical trials in TRD

The concept of switching antidepressant finally gained in importance when it came to a definition of TRD that could be used in clinical trials to demonstrate efficacy in TRD as a specific recognized indication. Lately, in response to the need to validate treatment strategies or specific medication in TRD, regulatory authorities both in Europe and in the United States elaborated their own recommendations to be used in clinical trials. Things were then significantly simplified, and for practical reasons TRD was defined as nonresponse to two consecutive trials of two different antidepressants at an adequate dose and duration. In this vision of TRD, what matters most is the switch in treatment. When, how and with which other antidepressant to make this switch?

At first, it was required to change antidepressant class. That is, using an antidepressant with a different mechanism of action than the one that did not work on the first attempt. This requirement was mainly based on clinical practice. It is more common to switch antidepressant classes in the hope of having a better chance of success. This practice, although theoretically meaningful, has never really been demonstrated through robust clinical data. The European Medical Agency (EMA) Guideline on clinical investigation of medicinal products in the treatment of depression consider monotherapy in patients with TRD as a separate claim and proposes clinical trial design and definition of TRD. TRD is considered, when treatment with at least two different antidepressant agents prescribed in adequate dosages for adequate duration and with adequate affirmation of treatment adherence showed lack of clinically meaningful improvement ( ). This pragmatic definition differs from the complex available staging models but is mainly intended to be used within clinical trials as a reference to characterize patients included based on the number and type of previous treatments. This definition differs from previous versions where two products of different pharmacological classes were requested. This important revision was in line with the data showing no advantage in favor of switching to a different class of antidepressant ( ; ; ; ).

The efficacy of Esketamine nasal spray, the newly approved medication in TRD was investigated using this definition of TRD ( ). As the study definition of TRD did not require the second antidepressant to be from a different class, a patient who had received two consecutive SSRIs or SNRIs was considered treatment resistant.

Switching within the same class or switching across classes?

Beyond theoretical considerations and the impact on the definition of TRD, the question of switching antidepressant class is fundamental from a practical standpoint. The history of this debate is supported by a limited number of studies, but most of them point in the same direction. The evidence in favor of using antidepressants from two different classes is weak. published the first metaanalysis on data comparing switching strategies for depressed patients who failed to respond to a SSRI, a second SSRI or a different class of antidepressant. Results suggested a marginal benefit of switching from one class of antidepressant to another on remission rates. It is worth mentioning that not all antidepressant classes have been considered but only Venlafaxine, Mirtazapine, and Bupropion have been included. Thereafter, several reports showed no advantage in favor of switching to a different class of antidepressant ( ). Evidences concerning the switch between SSRI and TCA classes are relatively limited: a between-class switch from SSRI to TCA response rates of approximately 16.5%–48.5% has been reported, with lower response rates in studies including treatment-resistant patients; for the between-class switch from TCA to SSRI response rates were of 4%–75%; finally, response rates of within-class TCA switch were 9% and 30% ( ). Concerning within-class SSRI, switch response rates varied between 26.7% and 72%. In a prospective randomized open study in TRD the effect of continuation with the same treatment or switching to a different class of antidepressant using the SSRI citalopram and desipramine, a tricyclic antidepressant which has predominant noradrenaline reuptake properties, a statistically significant inferiority of switching across class was observed ( ). Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial that included depressive patients who were switched to a second step antidepressant after a SSRI failure demonstrated that all treatments in the second step were comparable ( ). These included bupropion sustained release, sertraline and venlafaxine. The STAR*D trial is essential in understanding the different sequences of the trajectory of antidepressant treatments in TRD. The data from this study shed light on the prognosis of response to various antidepressant treatments following treatment failure ( ).

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