Treatment-Resistant Depression

Siegfried Kasper, Stuart A. Montgomery, Siegfried Kasper, Stuart A. Montgomery

• Publisher: Wiley-Blackwell
• Year: 2013
• Print ISBN: 9781119952909
• eBook ISBN: 9781118556733
• Edition: 1
• Topic: Medicina
• Subtopic: Psiquiatría y salud mental

Treatment-resistant Depress

Successful management of patients with treatment-resistant depression requires a thorough understanding of the biological basis for both the depression and its failure to respond to standard treatments. This book clearly and succinctly summarizes the latest scientific research and its applications in clinical practice.

A first step is a clear definition of what constitutes treatment-resistant depression so that clinical trials and other studies are using common criteria, enabling comparison and meta-analysis of their outcomes. The opening chapter reviews definitions and predictors of treatment-resistant depression originating from different fields and discusses their usefulness in clinical practice and clinical research. The next chapter proposes a new definition, adapting terminology from medicine.

Biological classification requires identification of genetic risk factors and gene variants have been identified as accounting for 50% of the variance in the clinical outcomes of antidepressant treatments. Chapter 3 describes several genes already associated with treatment-resistant depression and, while further work is needed to translate findings into clinical recommendations, suggests that genetic prediction of treatment resistance could become a widespread clinical reality within a few years.

Most patients with treatment-resistant depression will be treated pharmacologically, so three chapters review the latest evidence for pharmacological best practice in switching strategies for antidepressants, the role of antipsychotics and augmentation strategies to complement lithium.

There are two major alternatives to pharmacotherapy: neuromodulation and psychotherapy. The brain intervention chapter summarizes clinical research and experience with electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy. The final chapter reviews the literature pertaining to the effectiveness of various forms of psychotherapy in patients who have not responded to antidepressant pharmacotherapy, explaining that patients who have not responded to one or two trials of antidepressant medication have a 30%-50% chance of responding to a focused psychotherapy. It proposes indications for psychotherapy in treatment-resistant depression and summarizes general therapeutic principles.

Essential reading for all psychiatrists managing patients with this distressing disorder.

CHAPTER 1

Definitions and Predictors of Treatment-resistant Depression

Daniel Souery

European Centre of Psychological Medicine – PsyPluriel, Brussels, Belgium

William Pitchot

Department of Psychiatry, University of Liège, Liège, Belgium

Summary

Treatment-resistant depression (TRD) remains a common ­condition, with 50–60% of patients not achieving meaningful response following antidepressant treatment. The huge complexity of the phenomenon and the wide variety of parameters that must be taken into account make creating a definition ­possible, but several attempts have been proposed over the last 30 years. Many TRD staging models have been suggested, all of them intended to clarify the concept of TRD, but the lack of consensus represents an ongoing clinical and nosological controversy. In parallel, efforts towards a more accurate definition are aimed at proposing clear-cut criteria for clinical trials and research to evaluate specific treatment strategies and biological factors in TRD.

Beyond a definition, efforts have been made to identify key clinical factors associated with TRD.

The purpose of this chapter is to review current available definitions and predictors of TRD originating from different fields and to discuss their usefulness in clinical practice and clinical research.

Introduction

Although TRD appears to be relatively common in clinical practice, the inconsistent way in which it has been characterized and defined remains a real problem, limiting systematic research. From a clinical point of view, TRD usually refers to an inadequate response to at least one antidepressant trial of adequate dose and duration. It is estimated that 50–60% of patients do not achieve meaningful response following antidepressant treatment (Souery et al., 1999). This conception may include a variety of clinical ­situations, from uncomplicated failure to one course of ­antidepressant to multiple failures with long-term persistence of depressive symptoms despite more complex treatments. The term treatment refractoriness is ­generally used in these ­circumstances. While this approach corresponds to the clinical reality, it doesn’t help to define TRD and to predict which depressive episode will be resistant to treatment. The huge complexity of the phenomenon and the wide variety of p­arameters that must be taken into account make creating a definition possible, but several attempts have been proposed over the last 30 years. Misdiagnosis (‘pseudoresistance’), comorbidities, definition of treatment response, treatment duration and ­compliance and the number of treatment failures are among the more difficult variables which need to be integrated in any attempt to characterize or define TRD, making this a real ­challenge (Fornaro et al., 2010).

Definitions of TRD have been considered from different ­perspectives and with diverse objectives. The available definitions are mostly proposed by clinicians who have in mind a direct benefit for difficult-to-treat patients. The identification of predictors for TRD shares the same concern. In ­parallel, efforts at providing a more accurate definition aim to propose clear-cut criteria for clinical trials and research in order to ­evaluate specific treatment strategies and biological factors in TRD.

The purpose of this chapter is to review current available definitions and predictors of TRD originating from different fields and to discuss their usefulness in clinical practice and clinical research.

Definition of TRD: historical perspective

The basic question that needs to be addressed in the proposed definitions remains the threshold at which we define ‘treatment resistance’. This threshold is composed of multiple complex variables, foremost among which is the number of ­antidepressant failures. Historically, two distinct periods can be recognized in the attempt to define TRD. The poor level of attention paid to conceptual examination in the 1970s and 1980s resulted in unsystematic research and uncontrolled clinical trials, which in turn led to a degree of confusion. An analysis of the existing publications on TRD highlights a long misty period; in a review of a 10-year period of the literature covering 1985–1995, more than 15 separate definitions were proposed (Ayd, 1983; Fawcett & Kravitz, 1985; Feigner et al., 1985; Fink, 1991; Links & Akiskal, 1987; McGrath et al., 1987; Montgomery, 1991; Nelsen & Dunner, 1993; Roose et al., 1986; Schatzberg et al., 1983, 1986; Thase & Rush, 1995). This first wave of definitions was influential in introducing key parameters such as dose (a minimal adequate dose equivalent of 200 mg of ­imipramine per day), duration of treatments and number of failures, but all of the definitions differed with respect to quantification of these parameters and the hierarchy of treatment types and sequences. At this time, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), lithium and electroconvulsive therapy (ECT) were among various treatments incorporated in any TRD definition, but all in different sequences and with ­various durations based on empirical assumptions. Feigner et al. (1985) proposed defining TRD as a failure to respond to either TCAs or MAOIs plus a duration of episode of at least 2 years; Links & Akiskal (1987) considered TRD a failure to respond to two TCAs, one MAOI, one ECT, one lithium and one heterocyclic trial; Fawcett & Kravitz (1987) introduced the need to apply various combinations of adequate trials of TCA, MAOI and ECT. Montgomery (1991) was the first to recommend a pragmatic approach of two antidepressant failures, anticipating the current most accepted description.

These proposals had the merit of setting the stage and emphasizing the need to propose a systematic approach in TRD. The challenge at that time was to propose clinical guidelines and treatment strategies and to initiate clinical and biological research in the field. The concept of TRD was not ready and mature enough to be considered for recognition by regulatory authorities in Europe or the USA, and no official indication for TRD was possible.

A new era opened with the emergence of more structured and practical definitions of TRD, giving priority to a descriptive approach that led to the staging models of TRD. Thase & Rush (1997) were the first to publish a comprehensive staging model, taking into account the number and class of treatments received in order to indicate the level of resistance. Lately, in response to the need to validate treatment strategies or specific medications in TRD, regulatory authorities in Europe and the USA have elaborated their own recommendations for use in clinical trials.

Besides the development of descriptive definitions, recent progress has been made in the identification of predictive factors for TRD. Combining such variables with the proposed definitions and staging models will certainly help to validate the concept of TRD.

TRD staging models

Several staging models have been proposed, all of them intended to clarify the concept of TRD. Although some overlap exits between these models, they mainly differ in the weight of quantitative and qualitative parameters considered. The current proposals have undoubtedly contributed to a better assessment of TRD, but the lack of consensus represents an ongoing clinical and nosological controversy (Fornaro et al., 2010).

Thase and Rush model (1997)

Faced with the heterogeneity of TRD, Thase & Rush (1997) proposed applying the concept of illness classification used in oncology. Their starting point was the most common situation: the failure of a selective serotonin reuptake inhibitor (SSRI) chosen as first-line treatment. More than a simple descriptive staging model, their guideline suggested a series of sequential strategies for each stage of resistance. The recommendations were primarily based on the available publications on the ­management of treatment nonresponse to SSRIs. Antidepressant nonresponders are classified along a five-stage continuum according to the number and class of antidepressants that have failed to provide a response. In the final algorithm, stage I resistance is considered a failure of at least one adequate trial of one major class of antidepressant.

The proposed model is then built based on the assumption that switching to an alternative medication with a different mechanism of action is appropriate. A hierarchy of treatments is implied with the statement that MAOIs are more effective than TCAs, and TCAs are superior to SSRIs. The authors also discuss the use of combination and/or augmentation strategies in the most difficult-to-treat situations, after more than two ­failures, but do not include these strategies in the staging model.

Stage II resistance is defined as a failure of at least two ­adequate trials of at least two distinct classes of antidepressant. Stage III is stage II resistance plus failure of an adequate trial of a TCA, stage IV corresponds to stage III plus failure of an ­adequate trial of an MAOI and stage V is stage IV plus a course of bilateral ECT.

Trying to integrate the simple descriptive approach of the level of treatment resistance to sequential treatment strategies is useful but raises important methodological issues. It is subject to discussion or controversy over the validity of the existing data on the efficacy of the treatment strategies; this is particularly illustrated by the issue of the current and more recent data not supporting the use of antidepressants from two different classes. However, this approach is commonly used in clinical practice and is recommended in several treatment guidelines (Bauer et al., 2007). The results of a recent meta-analysis comparing two switch strategies for depressed patients failing to respond to an SSRI, a second SSRI or a different class of antidepressant suggest a marginal benefit of switching from one class to another on remission rates only (Papakostas et al., 2008). In contrast, other groups reported no advantage of switching classes (Bschor & Baethge, 2010; Ruhé et al., 2006; Rush et al., 2006).

The Thase and Rush staging model is the first attempt to ­integrate evidence-based data on treatment strategies and level of resistance in a comprehensive model (Thase & Rush, 1997). It represents an easy-to-use tool, providing a logical ­representation of the levels of resistance for clinicians. Its limitations are that dosing and duration of each sequence are not defined, and that nonresponse to two agents of different classes is assumed to be more difficult to treat than nonresponse to two agents of the same class. It may need revision based on more recent data. In addition, the staging model is limited by the implicit hierarchy of antidepressants (MAOIs > TCAs > SSRIs), for which there is no sufficient evidence in the literature.

European staging model (1999)

The Group for the Study of Resistant Depression (GSRD) ­developed a quantitative and sequential staging model that does not integrate treatment strategies (Souery et al., 1999). Facing the complexity of definitely specifying the number of failed adequate trials needed to define resistance, the model proposes a simple continuum starting from the first antidepressant failure in the treatment of a depressive episode and continuing with all subsequent unsuccessful trials regardless of the type of treatment. The different stages correspond to the number and duration of antidepressant trials. This model is independent of the treatments used and does not imply a hierarchy of efficacy of antidepressants or treatment strategies. The controversial issue of the number and type of adequate therapeutic trials may be arbitrarily solved using this continuous-quantitative principle. The model is built on naturalistic observation of the outcomes of prescribed treatments. These operational criteria are not to be considered an absolute definition of TRD, but rather a logical instrument that can be used in clinical practice and research projects in order to classify patients based on their level of resistance.

The model proposes distinguishing between nonresponse and five levels of TRD. The starting point is the depressive episode for which lack of response is recognized and the type of drug for which resistance is observed. A single adequately treated episode of nonresponse to an antidepressant is in itself sufficient to raise the issue of resistance. Patients who do not respond to one type of adequately prescribed drug (e.g. an SSRI-resistant depressive episode) are classified as nonresponders to any antidepressant therapy....

Table of contents

• Cover
• Title page
• Copyright page
• List of Contributors
• Foreword
• CHAPTER 1: Definitions and Predictors of Treatment-resistant Depression
• CHAPTER 2: Treatment-resistant Depression: A Separate Disorder – A New Approach
• CHAPTER 3: Genetics of Treatment-resistant Depression
• CHAPTER 4: Is There a Role for Switching Antidepressants in Treatment-resistant Depression?
• CHAPTER 5: The Role of Atypical Antipsychotics in Inadequate-response and Treatment-resistant Depression
• CHAPTER 6: Lithium, Thyroid Hormones and Further Augmentation Strategies in Treatment-resistant Depression
• CHAPTER 7: The Role of Nonpharmacological Interventions in Treatment-resistant Depression
• CHAPTER 8: The Role of Psychotherapy in the Management of Treatment-resistant Depression
• Index