Elsevier

Pharmacological Research

Volume 139, January 2019, Pages 494-502
Pharmacological Research

Review
The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications

https://doi.org/10.1016/j.phrs.2018.10.025Get rights and content

Abstract

The re-emergence (i.e. ‘breakthrough’) of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic–pituitary–adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients.

Introduction

The phenotype of tolerance to antidepressant drugs during maintenance treatment of chronic anxiety disorders [1] and major depressive disorder (MDD) may occur in a significant proportion of patients [2], with the return of depressive symptoms of MDD occurring in 9–33% of patients across published trials [3]. The many drivers of this phenomenon and their mechanisms are complex and poorly understood.

Tolerance has been used as a label for a wide range of clinical phenomena characterized by a reduced therapeutic responsiveness to antidepressants following the prolonged and often successful use of these drugs as initial and maintenance treatments for MDD. Increasing the dosage of the antidepressant may re-amplify the drug’s effects [4]. However, this widespread clinical approach [5] may exacerbate tolerance and induce chronicity and refractoriness in a substantial subset of patients with MDD [6].

Some patients may also develop tolerance to antidepressant-related side effects, in which case tolerance could be a desirable outcome. In contrast, other patients may develop reverse tolerance (or drug sensitization) thus exhibiting a higher propensity to develop side effects over time even when exposed to low doses of antidepressants [7,8]. In addition, some of those adverse effects may be due to the so-called nocebo effect [9]. Tolerance may also occur after continuous treatment with an antidepressant drug that may recruit processes that oppose its initial acute effects over time; this phenomenon has been referred to as the oppositional model of tolerance [10].

Tachyphylaxis (Ancient Greek ταχύς, tachys, "rapid", and φύλαξις, phylaxis, "protection") is a type of drug tolerance referring to the sudden, short-term onset of loss of effect following the administration of a drug [11]. Interestingly, the concept of tolerance has implications beyond pharmacodynamic or pharmacokinetic aspects. Specifically, behavioral tolerance and sensitization towards clinical and psychosocial features (e.g. grief or other external life events) may likewise affect long-term outcomes of the pharmacological treatment for depression. This aspect suggests that “tolerance” could be a more suitable term than “tachyphylaxis” from a clinical standpoint [12].

Apart from the notable exception of the criteria proposed by Rothschild [13] (see Table 1), there are no univocal operational definitions for “tachyphylaxis” or other tolerance-related phenomena. Hence, concepts such as “poop-up/out” (response), “wear-off” (phenomena), “depressive recurrence during maintenance antidepressant treatment” (DRAT), “breakthrough” (depression), and “loss of efficacy” have been used interchangeably and inconsistently in the literature [11,14]. Supplementary Table S1 (available online) provides a detailed view of the proposed definitions for this complex set of phenomena.

This inconsistency is concerning, considering the clinical burden associated with the long-term course of MDD. Moreover, most trials assessing the efficacy, safety, and tolerability of antidepressants are of short duration (i.e., acute trials), while there is a relative paucity of long-term (i.e., maintenance) antidepressant trials. In addition, whenever assessed, maintenance antidepressant drug trials for MDD rarely exceeds 52-week duration [15], and thus uncertainty exists regarding the detrimental role of tolerance in increasing the likelihood of subsequent treatment-resistance to antidepressants despite initial response. Therefore, uncontrolled observational studies provide a significant amount of evidence pertaining to the emergence of tolerance over the course of antidepressant drug treatment for MDD.

During the past decades, several neurobiological and behavioral mechanisms and hypotheses have been implicated in the emergence of tolerance to antidepressant drugs during the treatment of MDD ranging from pharmacokinetics, pharmacodynamics and adaptive models. Nonetheless, additional insights are needed to shed light on such a complex phenomenon.

While this paper focuses on the mechanisms of antidepressant tolerance per se, it is important to note that many causes of perceived loss of treatment efficacy and not pharmacokinetic in origin. Bipolar disorder, if latent and undiagnosed in the context of a depressive presentation is much more commonly associated with antidepressant “poop out” [16], and that phenotype is regarded by many as suggestive of a latent bipolar phenotype possibly affecting the response to the antidepressant drugs [17]. Stressors and life events can intrude, and cause depression despite previously adequate maintenance efficacy. Neuroprogression of the underlying disorder is associated with treatment resistance. Comorbidities such as substance use disorder can undermine previously effective maintenance therapy [18], although the actual impact of varying potentially contributing factors is yet to be fully appraised. Finally, there is a narrow gap between antidepressants and placebo in acute treatment trials, implying that many people who improve while taking antidepressants are placebo responders. In these people, perceived loss of efficacy may actually be a loss of the placebo effect. But it is equally true that a proportion of people on long-term antidepressants retain robust prophylactic efficacy over time, and the differential neurobiology and clinical phenotype of these groups are not clearly delineated.

The present comprehensive review critically appraises existing evidence about tolerance to drugs for depression. To the best of our knowledge, the present review is the first of its kind to critically appraise the different definitions documented in the literature, attempting to provide a unitary definition for this phenomenon. In order to do so, the present review integrates a critical perspective on the putative mechanisms of tolerance and related phenomena that may emerge over the course of the pharmacological treatment of MDD. In addition, clinical correlates and implications are critically evaluated as an attempt to direct future research and the clinical practice.

Section snippets

Search strategy and selection criteria

The following keywords or their combination were searched for results indexed in PubMed since inception through July 23rd, 2018: (((((("antidepressant tolerance"[Title/Abstract]) OR "antidepressant poop out"[Title/Abstract]) OR "antidepressant poop up"[Title/Abstract]) OR "antidepressant tachyphylaxis"[Title/Abstract]) OR "loss of efficacy"[Title/Abstract]) OR "antidepressant withdrawal"[Title/Abstract]) OR "antidepressant wear-off"[Title/Abstract]) OR "breakthrough depression"[Title/Abstract].

Frequency and clinical correlates of tolerance to antidepressants during the treatment of MDD

The actual rates of tolerance to antidepressant agents and related phenomena remain unclear. This is to a large extent due to the heterogeneity of definitions across the existing literature as well as the co-occurrence of other causes of antidepressant resistance. Moreover, the true rates of tachyphylaxis occurring during continuation treatment with drugs for depression for MDD may be lower than once thought [19], based on the method developed by Quitkin and colleagues in the early 1990s for

Potential mechanisms and models of tolerance to antidepressants

The mechanisms of tolerance to antidepressant drugs are yet to be fully elucidated. Nonetheless, converging evidence suggests a multifactorial and complex origin involving the interplay of both neurobiological and psychosocial mechanisms. Multiple possible neurobiological explanations for the emergence of tolerance to antidepressants and related phenomena have been proposed. For instance, it was postulated that the activation of processes driving tolerance to antidepressant drugs may occur to

Critical appraisal of the evidence

In 2001, Ghaemi et al. adopted the label of “antidepressant view of the world”, referring to an increase in research interest and a sharp increase in the prescription of antidepressant drugs worldwide [73] as being the (by) product of what Ross Baldessarini conceptualized as the “pharmaco-centric view of the world” in the year 2000 [74], based on the historical contributions of Klerman [75,76]. According to their claims, these latter prominent researchers prompted-out for the risk of

Conclusion and outlook

This review provides evidence that the emergence of tolerance during long-term antidepressant drug treatment may contribute to worse outcomes in a subset of patients with depression. At the same time, it outlines a lack of consensus in the literature regarding the operational definition for this complex clinical phenomenon and its confounds. This aspect hinders a more precise appreciation of the frequency and correlates of tolerance to antidepressants. Particularly, well-designed maintenance

Disclosure statement

EV has received grants and served as a consultant, advisor, or CME speaker for the following entities: AB-Biotics, Allergan, AstraZeneca, Bristol-Myers-Squibb, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefonica, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (Centro de Investigación Biomédica en Red de Salud Mental), the Seventh European

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