Treatment-resistant depression is associated with significant disability and, due to its high prevalence, results in substantive economic and societal burden at a population level. The objective of this study is to synthesize extant literature on approaches currently being applied to understand and address this condition. It is hoped that the findings can be used to inform practitioners and guide future research. A scoping review of the scientific literature was conducted with findings categorized and charted by underlying research paradigm. Currently, the vast majority of research stems from a biological paradigm (81%). Research on treatment-resistant depression would benefit from a broadened field of study. Given that multiple etiological mechanisms likely contribute to treatment-resistant depression and current efforts at prevention and treatment have substantial room for improvement, an expanded research agenda could more effectively address this significant public health issue. 1. Introduction Of the population receiving treatment for depression, a large proportion is not responding adequately to current treatment approaches, with an estimated 50–70% described as treatment resistant [1, 2]. A consistent and commonly accepted definition for treatment-resistant depression (TRD) remains elusive. Greden [1] argues that remission should be the ultimate goal of treatment and absence of remission should be the criterion used for determining the presence of TRD. Berlim and Turecki have noted over 10 different definitions for TRD in the specialized literature [3, 4]. However, in a systematic review of randomized trials ( ), they report a general consensus within the literature defining clinically significant TRD as “an episode of major depression (that) has not improved after at least two adequate trials of different classes of (antidepressants)” ( ) [4, page 703]. The authors further argue that TRD should be viewed on a continuum ranging from partial response to complete treatment resistance as opposed to an all or nothing phenomenon. They point out that an inadequate response to treatment should constitute failure to reach remission, and that future studies should employ this criterion as the “gold standard outcome,” a conclusion that parallels Greden’s work [1]. Fava defines TRD as a failure to achieve remission following an adequate trial of antidepressant therapy [5]. This definition differs from that proposed by Berlim and Turecki in that it does not necessitate two adequate trials of antidepressant treatment [3, 4]. Like other TRD researchers [1, 3,
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