Treatment-Resistant Depression: An Overview of the Problem

David L. Dunner, MD, FACP

Dr. Dunner is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences, and director of the Center for Anxiety and Depression at the University of Washington in Seattle.

Disclosure: Dr. Dunner is a consultant to Bristol-Myers Squibb, Corcept, Cypress, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, Shire, Somerset, and Wyeth; is on the speaker’s bureaus of Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, and Wyeth; and has received grant support from Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Pfizer, and Wyeth.

Please direct all correspondence to: David L. Dunner, MD, FACP, Center for Anxiety and Depression, 4225 Roosevelt Way N.E., Suite 306-C, Seattle, WA 98105-6099; Tel: 206-543-6768; Fax: 206-543-7565; E-mail: [email protected].

Abstract

Treatment-resistant depression (TRD) is a common public health problem. This article presents an overview of issues related to TRD. These issues can be summarized in terms of several “D’s.” How is TRD Diagnosed? How is TRD Determined? Are there Diagnostic issues in TRD? Has the Dose and Duration of treatment been adequate? What is the putative mechanism of action of the Drug and how best to apply a Different treatment. Furthermore, characteristics of treatment-resistant depressives who were followed over a 1-year period with naturalistic treatment is discussed.

Introduction

This article presents an overview of treatment-resistant depression (TRD). Depression is a common mental health problem and most patients with depression are treated in primary care settings. The response to treatment in such settings is fairly high; it is thought that 50% to 75% of patients will respond to treatment for depression in a primary care setting. 1 This, however, leaves a considerable percentage of patients who do not respond and who might be considered treatment resistant. Such patients are frequently referred to psychiatrists in order to implement various strategies regarding improving their condition. Thus, TRD is a common problem that psychiatrists encounter.

Definitions

There is no standard definition for TRD. Operational definitions of TRD usually entail the inverse of treatment response. In research clinical trials of depression, the definition of response that is commonly used is a decrement of 50% of a rating scale measure (often the Hamilton Rating Scale for Depression) from baseline to endpoint of the clinical trial. 2 A second definition, which is clinically based, would focus on failure of one or more treatment trials. A third definition involves persistence of depressive symptoms and failure to attain remission during treatment, thus differentiating response from remission. All of the above definitions are predicated on some degree of adequacy of treatment. Thus, another group of patients who have failed to respond or achieve remission to treatment but who were inadequately treated might be included as treatment resistant. Additionally, patients who are not able to tolerate antidepressant medications because of side effects might also be included in a treatment-resistant group, even though they also have not had adequate treatment trials. It is clear from above that there needs to be standardization of the definition of the term “treatment resistance” since outcome definitions can vary from setting to setting. In the clinical setting, rating scales are infrequently employed to assess response. Although the figure of 50% to 70% of depressed patients is cited as a response rate to treatments, the remission rate (at least from research clinical trials) is approximately 30% to 40%. 3 In order to calculate how many patients might be treatment resistant, one could cite the 30% or so who failed to show response as one group or the 60% to 70% initially treated who failed to achieve remission. However one wishes to calculate the percentage of patients who were initially treated for depression and who show some signs of treatment resistance, the resulting figure is considerable and accounts for a high proportion of depressed patients.

Definitions of treatment resistance in bipolar disorder are also not well-agreed upon. Dunner and Fieve 4 reported that rapid-cycling patients comprised a large percentage of bipolar patients who showed recurrence of mania, hypomania, or depression during a maintenance trial of lithium carbonate.

There are four target treatment areas of bipolar disorder: acute mania, acute bipolar depression, maintenance against mania, and maintenance against depression. 5 For rapid cyclers, it is the maintenance effect that is noted. However, there may be treatment-resistant patients for the acute phases of the illness as well. Cole and colleagues 6 proposed four patterns of treatment resistance in bipolar disorder: rapid cycling, slower cycling, chronic depression, and mixed states. Sachs 7 proposed a definition of treatment-refractory bipolar depression as “a depression without remission despite two adequate treatments of standard antidepressant agents for 6 weeks each, with or without augmentation strategies.” 7 More recently, Vo and Dunner 8 studied a group of treatment-resistant bipolar disorder patients defined as “those who had failed at least one treatment trial.” In comparing rapid cycling and non-rapid cycling bipolar patients who were treatment resistant, they found very few clinical differences. Chronic depression was a problem among both rapid and non-rapid cycling patients. Misdiagnosis of their illness also occurred and for the most part, non-rapid cyclers had resistance to depression as their major difficulty, rather than continued cycling or failure to show a response to treatment of mania. Inadequate history of lithium treatment was found for both the rapid cycling and non-rapid cycling patients.

Assessment of Treatment Resistance

Csernansky and Hollister 9 proposed examining five factors: Diagnosis, Dose, Duration of treatment, what is the putative mechanism of the Drug, and to apply a Different treatment. These “D’s” of treatment resistance should be assessed in all treatment-resistant patients. These factors, diagnosis, dose, duration of treatment, and repeated application of drugs of the same putative mechanism, are frequently found in studies of defined treatment-resistant patients. Again, there is no consensus regarding definitions of many of these terms. For example, there is no established minimal adequate dose, although twice the recommended starting dose for adults might be considered “adequate.” Furthermore, recommendations regarding duration of treatment vary from 4–12 weeks for an “adequate” trial. Switching medications within a class (ie, selective serotonin reuptake inhibitor [SSRI] to SSRI) may benefit some patients. 10 Switching medications to a different class is likely to show greater benefit. 11

Staging of treatment resistance for major depression has been proposed by Thase and Rush (Table). 12 These five stages represent increasing complexity of treatment nonresponse. However, many patients fail to respond to multiple trials of antidepressants in the same class. For example, many patients are nonresponders to multiple SSRI treatments and therefore, would continue at Stage I in the Thase and Rush classification. More recently, we proposed a classification of treatment resistance based on adequacy of treatment. “Simple treatment resistance” would involve a minimal number of trials, low doses, brief duration using the same class of medication, or perhaps failure to two treatment trials of antidepressants from the same class (ie, failure to respond to two SSRIs). “Complicated treatment resistance” would be failure to respond to three or more adequate treatment trials, which might include augmentation trials and would certainly involve antidepressants from different classes.

Characteristics of Treatment Resistance

An earlier study from our group of TRD patients referred to the Center for Anxiety and Depression revealed that there was a higher frequency of suicide attempts in TRD as compared to non-TRD patients. 13 TRD patients were more likely to have chronic depression. Approximately one third of patients were misdiagnosed, approximately one third had brief treatment trials, and approximately one third of the trials involved an ineffective (low) dose. There was also a low utilization (18%) of electroconvulsive treatment in that population.

Recently, a second large group of TRD patients has been studied over a 2-year follow-up period. 14 Patients who were treatment resistant and had failed an average of over three clinical trials for the current major depressive episode were involved in this study (N=127). Once assessed by the research team, patients were treated by their clinicians utilizing usual standards of care and returned for follow-up research assessments of mood and health care utilization every 3 months. In spite of vigorous treatment during the first year of follow-up, only approximately 12% of patients responded and fewer than 10% achieved remission.

Primary Care Issues

The issue of underdiagnosis of depression in primary care settings deserves some comment. The “50% rule” seems to pertain to most studies of depression in primary care, namely, only approximately 50% of patients with depression are diagnosed in the primary care setting. Of those, only approximately 50% are treated, and of those treated, only approximately 50% receive adequate treatment. 15 Thus, increased recognition in primary care and improvement of treatment practices would likely decrease the probability of some patients not showing response to treatment. It would also likely increase the number of patients presenting to psychiatrists since in any given treatment paradigm, greater numbers of depressed patients who are treated would result in an absolute increase in the number of patients who might be treatment resistant.

Consequences of Failure to Achieve Remission

It is clear that failing to achieve remission worsens long-term outcome. A study by Judd and colleagues 16 and a study by Paykel and colleagues 17 demonstrated that patients who had not remitted from their index depressive episode showed greater tendencies toward relapse and recurrence and also had greater psychosocial morbidity.

Interestingly, a biological factor involved in depression might also cause concern regarding failure to achieve remission in depressed patients. There has been a hypothesis that corticosteroid hormone output is increased in depression. 18 The increased corticosteroid output may be associated with hippocampal atrophy. 19 This research highlights the role of brain-derived neurotropic factor, which may be increased during antidepressant treatment, thus increasing size or numbers of brain cells and effectiveness of brain function. 20 Another biological factor relates to the possibility of the serotonin transporter gene and its polymorphisms possibly being related to TRD, although this finding requires further research. 21

Summary

TRD is an important clinical problem. Continued depression results in increased healthcare utilization and psychosocial functioning impairment. It is also a problem increasingly confronting psychiatrists regarding the need for establishing a correct diagnosis and appropriate treatment trials in order to improve the outcome of patients with depression. TRD is an area that is largely understudied, but has been increasingly studied in the last few years. Most of the studies have focused on patients with unipolar or major depression, but some studies have also included patients with bipolar depression. As new and effective treatment approaches emerge for TRD, greater attention will need to be paid by the clinician regarding how to sequence these treatments most effectively in order to maximize benefit. PP

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