DEFINITION AND EPIDEMIOLOGY OF TREATMENT-RESISTANT DEPRESSION

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The main goal of treatment in patients with mood disorders is usually to restore a state of psychological wellness and high functioning. Although many depressed patients do improve with adequate antidepressant treatment, a significant proportion fail to reach acceptable levels of functioning and well-being. The most simplistic definition of treatment resistance is the failure to achieve and sustain euthymia with adequate antidepressant treatment. Currently, however, there is no universally accepted definition of treatment resistance in unipolar depression.84 This is partly due to the evolving nature of current psychiatric practice, which is continually refined by consensus or official clinical research. Additionally, as mentioned by Dyck,22 most uses of the term resistance reflect the expectations or assumptions of a given clinician about a person's response to treatment. Thus, the definition of treatment resistance in depression may vary widely.

It is generally agreed that adequacy of treatment is a central issue in the definition of treatment resistance. In medicine, the phrase “resistance to treatment” is used to define patients failing to respond to a standard form of treatment. One would certainly not use the phrase resistance to antibiotic treatment to characterize individuals whose bacterial infections were treated for only 2 days with very low doses of penicillin. Similarly, in psychiatry, the term treatment-resistant depression should apply only to depressions that do not resolve after antidepressant treatment in adequate doses (or intensity) and for a time sufficient for response. Although such a definition can be used in patients who have been treated with pharmacologic, nonpharmacologic, or combined treatment approaches, most of the literature on treatment-resistant depression has based its definition of resistance on the failure to respond to antidepressant drug treatment of adequate dose and duration. The answer to what constitutes an adequate treatment trial, however, depends on what specific expectations for treatment outcome are appropriate.22 It may be unrealistic to expect that a single monotherapeutic trial with an antidepressant would lead to remission of major depression in a patient with comorbid psychiatric disorders and significant psychosocial stressors. On the other hand, it is reasonable to assume that an antidepressant drug trial of adequate dose and duration should be effective in patients suffering from major depressive disorder.

As mentioned previously, several other variables may influence resistance to pharmacotherapy. When treatment-resistant depression is defined as the failure to respond to antidepressant drug treatment, two other factors need to be considered when establishing the adequacy of treatment: compliance with treatment (i.e., is the patient taking the medication as prescribed?) and the appropriateness of plasma drug levels (for tricyclic antidepressants only), as there seems to be a significant relationship between response rate and tricyclic antidepressant plasma levels.77

A review by Scott88 of various definitions of treatment-resistant depression found a marked lack of agreement on the standards and range of treatments required before declaring treatment resistance. Whereas several studies18, 39, 79, 87 clearly have established that antidepressant treatments of short durations (i.e., 4 weeks) do not represent an adequate period to establish whether a drug treatment is effective, the concept of adequate dose varies greatly across different investigators.88 For example, although Lehmann56 suggested that 150 mg/day or its equivalent given for 4 to 6 weeks is an adequate dose for tricyclic antidepressants, Guscott and Grof40 recommended higher doses (up to 300 mg/day for 6 weeks) for the same class of antidepressants.

In this article, we propose an operational definition of treatment-resistant depression and discuss partial and nonresponse, as well as the methodologic issues that emerge in the assessment of resistance. Finally, we review possible predictors of failure to respond and attempt to estimate the prevalence of treatment-resistant depression by reviewing the results of recent clinical trials with antidepressant medications in unipolar major depressive disorder.

Section snippets

DEFINITION OF TREATMENT RESISTANCE

Treatment-resistant depression patients may be defined as those who fail to respond to standard doses (i.e., significantly superior to placebo in double-blind studies) of antidepressants administered continuously for a minimum duration of 6 weeks. This definition of treatment-resistant depression, although more liberal than some, has the advantage of taking feasibility of treatment into account. For example, 12 continuous weeks of monotherapy would be a more conservative definition for the

TREATMENT RESISTANCE VERSUS RELAPSE OR RECURRENCE

A recent review102 illustrated that much of the literature on treatment-resistant depression has failed to distinguish between the concepts of resistance (failure of the current episode to remit) and the concepts of relapse or recurrence (return of symptoms to the point of meeting criteria for major depressive episode after an initial response). These concepts often cannot be distinguished on the basis of their clinical features without a longitudinal assessment. To complicate this issue

NONRESPONSE VERSUS PARTIAL RESPONSE

Clinical studies of antidepressant drug treatments clearly have shown that many depressed patients improve significantly with treatment but still do not reach acceptable levels of functioning and well-being. These patients often are referred to as partial responders as opposed to nonresponders (i.e., those who show little or no improvement with treatment). Similarly, Frank et al36 used the term partial remission to describe a period during which an improvement of sufficient magnitude is

PROSPECTIVE VERSUS RETROSPECTIVE ASSESSMENT OF TREATMENT RESISTANCE

One of the major methodologic issues in treatment-resistant depression studies is whether assessment of resistance is performed prospectively or retrospectively. The prospective method of determination of treatment resistance is clearly preferable as there is a tremendous risk for misclassification with retrospective determination. Possible recall biases are likely to greatly affect patients' self-report of response to previous drug trials. Such recall bias becomes quite evident in clinical

CHRONICITY VERSUS TREATMENT RESISTANCE

An important distinction needs to be made between treatment-resistant depression and chronic depression. The term chronic refers to a prolonged, lingering condition and is derived from the Greek word chronos, or time, whereas treatment resistance connotes a condition that is difficult to treat regardless of its duration.59 Chronicity may appear as a protracted major depressive episode, as unremitting dysthymia, or as subsyndromal depression. Although chronicity may be the result of true

OTHER METHODOLOGIC ISSUES IN THE ASSESSMENT OF TREATMENT RESISTANCE IN DEPRESSION

Dyck22 has proposed that one of the major problems in assessing treatment resistance in depression is the failure to adequately conceptualize or specifically define treatments. When examining resistance to treatment, clinicians must focus on the efficacy of acute treatment only to avoid the risk of misclassification of relapses or recurrences as failure to respond. The acute treatment phase is defined as the period beginning with the diagnosis of a mood disorder episode and ending after

PREDICTORS OF NONRESPONSE OR PARTIAL RESPONSE IN DEPRESSION

As mentioned by Paykel73 in a review of the literature, attempts to use biologic markers as predictors of failure to recover have not yet been successful. Significantly shortened REM latencies, however, may predict treatment resistance.53 There are also a number of clinical factors, including some specific subtypes of major depression, that have been found to predict poorer response to antidepressant treatment. For example, family history of affective illness appeared to predict worse outcome,2

EPIDEMIOLOGY OF TREATMENT-RESISTANT MAJOR DEPRESSIVE DISORDER

Even though the prevalence of depression has been reported to vary from 2.6% to 5.5% in men and from 6.0% to 11.8% in women,57 no study has assessed systematically the epidemiology of treatment-resistant depression. For this reason, we decided to attempt to generate estimates of the prevalence of treatment resistance in populations with unipolar major depressive disorder through a compilation of rates of partial response and nonresponse in recently published clinical trials. Because most

SUMMARY

Our results suggest that between 29% and 46% of depressed patients fail to respond fully with antidepressant treatment of adequate dose and duration. In particular, although partial response appears to occur in 12% to 15% of the depressed patients studied, nonresponse is observed in 19% to 34% of this population. The prevalence of treatment-resistant depression derived from studies using ITT analysis is likely to be an overestimate of the actual occurrence of the phenomenon, as these rates also

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    Address reprint requests to Maurizio Fava, MD, Clinical Psychopharmacology Unit, Massachusetts General Hospital, 15 Parkman Street WAC 815, Boston, MA 02114

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    From the Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts

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