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Incidence, Impact, and Current Management Strategies for Treatment-Resistant Major Depressive Disorder

Authors: George I. Papakostas, MDFaculty and Disclosures


Definition of Treatment-resistant depression

Treatment-resistant depression (TRD) typically refers to an inadequate response to at least 1 antidepressant trial of adequate dose and duration among patients suffering from major depressive disorder (MDD). Adequate duration is often defined as a minimum of 6 weeks of treatment.[1] This definition stems from the observation that fewer than 7% of patients who show little improvement following 6 weeks of treatment with fluoxetine eventually respond (50% decrease in symptom severity) following an additional 2 weeks of treatment,[2] while only 12% of patients who show little or no improvement following 6 weeks of treatment experience at least a partial response following an additional 2 weeks of treatment.[3] Although similar analyses of clinical trials of longer duration (12 weeks) have provided evidence arguing that 6 weeks may be too short a duration to declare an antidepressant trial ineffective,[4] it is also important to keep in mind that spontaneous remission rates can be substantial over time and, therefore, the degree to which delayed onset of clinical improvement (ie, after week 6) is due to a "true" antidepressant effect vs spontaneous remission of symptoms is questionable.[5,6] However, it is also worth pointing out that the original analyses by Nierenberg and colleagues[2] were based on data derived from a fixed-dose trial of fluoxetine 20 mg/day, and that delayed dose escalations are likely to affect how long clinicians need to wait before they assume that the duration of the trial is adequate. The definition of adequate dose varies widely from agent to agent, with values deriving from double-blind, placebo-controlled trials or dose-comparator studies.[1]

Definitions of "adequate response" have varied throughout the course of the past few decades, ranging from the more traditional view in which treatment-resistance is defined as strict nonresponse, to the broadest definition; ie, failure to achieve full symptom remission.[7] Nowadays, most experts agree that inadequate response is the failure to achieve full symptom remission for several reasons.[1] First , as first pointed out by Nierenberg and Amsterdam,[8] patients presenting with moderate-to-severe depression may still be quite symptomatic despite a 25%-50% improvement in depressive symptoms. In addition, residual symptoms have been associated with poorer psychosocial functioning[9], as well as increased relapse rates.[10] Finally, incomplete response (defined as a 25% or greater improvement in depressive symptoms failing to achieve remission) appears to be more than twice as common as strict nonresponse in naturalistic treatment settings (28.7% vs 12.9%, respectively).[11] Therefore, defining TRD as strict nonresponse following adequate treatment rather than failure to achieve remission would actually exclude the majority of patients who have not been successfully treated.

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