Elsevier

Biological Psychiatry

Volume 53, Issue 8, 15 April 2003, Pages 649-659
Biological Psychiatry

Difficult-to-treat depression
Diagnosis and definition of treatment-resistant depression

https://doi.org/10.1016/S0006-3223(03)00231-2Get rights and content

Abstract

Treatment-resistant depression (TRD) typically refers to inadequate response to at least one antidepressant trial of adequate doses and duration. TRD is a relatively common occurrence in clinical practice, with up to 50% to 60% of the patients not achieving adequate response following antidepressant treatment. A diagnostic re-evaluation is essential to the proper management of these patients. In particular, the potential role of several contributing factors, such as medical and psychiatric comorbidity, needs to be taken into account. An accurate and systematic assessment of TRD is a challenge to both clinicians and researchers, with the use of clinician-rated or self-rated instruments being perhaps quite helpful. It is apparent that there may be varying degrees of treatment resistance. Some staging methods to assess levels of treatment resistance in depression are being developed, but need to be tested empirically.

Introduction

Treatment-resistant depression (TRD) typically refers to the occurrence of an inadequate response following adequate antidepressant therapy among patients suffering from unipolar depressive disorders. What constitutes inadequate response has been an object of considerable debate in the field, and most experts nowadays probably would argue that inadequate response is the failure to achieve remission. Although the more traditional view of treatment resistance has focused on nonresponse (e.g., patients who have reported minimal or no improvement with drug therapy), from the perspective of clinicians and patients/consumers, not achieving remission despite adequate treatment represents a significant challenge. In addition, response without remission has a potentially poorer outcome, as residual symptoms are associated with poorer outcome and increased relapse risk Judd et al 1998, Van Londen et al 1998. Finally, response without remission following antidepressant treatment is associated with a significantly greater number of somatic symptoms than remission (Denninger et al 2002) and with impaired social functioning (Paykel 2002). For these reasons, it has been argued that “complete remission should be the goal in the treatment of patients with major depressive disorder (MDD), because it leads to a symptom-free state and a return to premorbid levels of functioning (Bakish 2001).” With this treatment approach in mind, inadequate response implies that the treatment failed to achieve remission. Several operational definitions of remission have been proposed (Frank et al 1991), but, from the clinician’s and patient’s perspective, remission typically implies achieving a relatively asymptomatic state.

Section snippets

What constitutes adequate antidepressant therapy?

Adequate antidepressant therapy is typically considered to consist of one or more trials with antidepressant medications with established efficacy in major depressive disorder. In addition, such trials need to involve doses considered to be effective (e.g., superior to placebo in controlled clinical trials) and their duration needs to be sufficient to produce a robust therapeutic effect (e.g., 12 weeks) (Quitkin et al 1986).

Are there several degrees of resistance to treatment in depression?

Since treatment resistance in depression typically concerns the occurrence of an inadequate response following adequate antidepressant therapy, it is apparent that the number of failed adequate antidepressant trials may range from one to countless. Are the chances of responding to antidepressant treatment gradually diminishing with the number of failed trials? There is a clear need to define the level of resistance. One may argue that a staging method of assessing resistance in depression may

The Thase and Rush model of staging treatment resistance

Thase and Rush (1997) first proposed a model of staging the various levels of resistance in TRD (Table 1). This model could be a very useful tool in the classification of treatment resistance in depression, although its predictive value with respect to treatment outcome has not yet been assessed systematically. On the other hand, there are several methodological issues with respect to this staging model.

First, the degree of intensity of each trial in terms of dosing and/or duration is not

Standard definition of stage 1 treatment-resistant depression

The most common definition of stage 1 TRD is that of inadequate response (i.e., failure to achieve remission) to at least one antidepressant trial of adequate dose and duration (Fava and Davidson 1996). This definition has typically included an operational classification of the degree of treatment resistance (Fava and Davidson 1996): 1) nonresponse (< 25% symptom reduction from baseline); 2) partial response (25% to 49% symptom reduction from baseline); and 3) response without remission (50% or

Alternative definition of stage 1 treatment-resistant depression

An alternative definition of stage 1 TRD has been proposed by North American, European, and Australian researchers Souery et al 1999, Burrows et al 1994. These investigators define TRD as a major depressive episode with poor response to two adequate trials of different classes of antidepressants. Although somewhat more conservative than the definition mentioned earlier, there are some methodological issues that concern this definition: 1) it is assumed that nonresponse to two agents of

The Massachusetts General Hospital staging method to classify treatment resistant depression

Given the issues mentioned above concerning the Thase and Rush (1997) staging method, we decided to propose a slightly different method (Table 2), which would take into consideration both the number of failed trials as well as the intensity/optimization of each trial, but would not make assumptions regarding a hierarchy of antidepressant classes. This method generates a continuous variable reflecting the degree of resistance in depression, with higher scores indicating greater treatment

Pseudoresistance

The term pseudoresistance (Nierenberg and Amsterdam 1990) has been used in reference to nonresponse to inadequate treatment, in terms of duration or dose of the antidepressant(s) used. One needs to ascertain whether any patient presenting with inadequate response to antidepressant treatment has received adequate antidepressant treatment. Did the patient receive antidepressant treatment for at least 8 to12 weeks? Were the doses prescribed in the therapeutic range? Did the patient take the

Depressive breakthrough: a special form of treatment-resistant depression

A special form of TRD is represented by the return of depressive symptoms during continued antidepressant treatment. The term “depressive breakthrough” has been used to describe this common clinical occurrence (Nierenberg and Alpert 2000). In fact, relapses and recurrences during continued antidepressant treatment appear to occur at rates between 10% and 30% (Fava and Kaji 1994). Typically, relapses and recurrences during antidepressant treatment are not included in the traditional definition

Predictors of resistance to a single antidepressant treatment

A number of clinical and sociodemographic variables have been studied in relationship to resistance to antidepressant therapy. The search of valid and robust predictors of resistance to a single antidepressant treatment has been filled with frequently inconsistent findings (Joyce and Paykel 1989). This is partly due to the fact that many published predictor studies were rather small, while large sample sizes are needed to establish with confidence the relationship between a given predictor and

Predictors of resistance to multiple antidepressant trials or electroconvulsive treatment

Very few studies have attempted to identify predictors of poorer outcome among depressed patients already identified as resistant, partly because of the relative paucity of clinical trials in treatment-resistant depression and partly because of the relative small sample sizes of such studies. In addition, such as in the case of resistance to a single treatment, it is not clear that predictors are independent of the types of treatment and their algorithm. For example, it is not clear whether a

How should clinicians evaluate resistance in depression?

A basic requirement in assessing resistance in depression is the accuracy of the diagnosis. Misdiagnosis can be a relatively common problem in clinical practice and it is often difficult to establish retrospectively whether the diagnosis of depression was accurate. One typical approach to this problem is that of completing a diagnostic re-evaluation, ideally with a structured clinical interview, so that psychiatric comorbidity is also systematically assessed.

It is also important to assess the

How should researchers assess resistance to antidepressant treatment?

As mentioned earlier, a basic requirement in assessing resistance in depression studies is the accuracy of the diagnosis. It is important to require reliability and validity in the diagnostic assessment used. This is relatively easily obtained in studies using a prospective assessment of resistance, typically by using structured clinical diagnostic interviews.

Another important step toward the assessment of resistance in depression concerns the level of drug treatment adherence. While a

Other methodological issues in treatment-resistant depression research

The most significant issue is probably that of the heterogeneity of the studied population. The heterogeneity of the population concerns a number of domains, ranging from the number of previous failed trials, intensity and duration of each trial, and clinical characteristics of the population itself. One particular aspect of clinical variability concerns the degree of psychiatric and medical comorbidity. Studies of drug treatment in TRD populations rarely adjust for the degrees of medical and

What about failure to respond to psychotherapy?

Since there is good evidence that certain forms of time-limited psychotherapy, such as cognitive-behavioral therapy and interpersonal therapy, are efficacious in the treatment of major depressive disorder (Jarrett et al 1994), one can argue that our current view of what constitutes an adequate antidepressant therapy is somewhat narrow and pharmaco-centric. In addition, it does not reflect the clinical utility that the depression-focused psychotherapies (interpersonal, cognitive, and behavioral)

Conclusion

TRD is a relatively common occurrence in clinical practice, with up to 50% to 60% of patients not achieving adequate response following antidepressant treatment. A diagnostic re-evaluation is essential to the proper management of these patients. In particular, the potential role of several contributing factors, such as medical and psychiatric comorbidity, needs to be taken into account. An accurate and systematic assessment of TRD is a challenge to both clinicians and researchers, and a number

Acknowledgements

Aspects of this work were presented at the conference, “Difficult-to-Treat Depression,” held April 21–22, 2002 in San Francisco, California. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted grant provided by Eli Lilly and Company.

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