Treatment-resistant depression: recent developments and future directions

Abstract

A significant proportion of patients with major depressive disorder (MDD) fail to achieve remission with standard antidepressant therapies, even when optimally delivered. These patients are classified as treatment-resistant depression (TRD), which is distinguished from “difficult-to-treat” depression,[1] defined as depression treated under circumstances that precludes the optimal delivery of a potentially beneficial treatment (e.g., subtherapeutic dosing, intolerable side effects, poor adherence, etc.) TRD is also distinguished from severe depression, as some patients with milder depressive symptoms are markedly treatment resistant, while others with profound, acute depressive symptoms are quite treatment responsive. Defining the boundaries of TRD is critical from a clinical, research, and public health perspective, as drug and device manufacturers seek new regulatory approvals for numerous indications in the TRD spectrum. This article reviews recent developments in TRD, with a focus on classification methods used for regulatory clinical trials; treatments currently approved in the US for TRD; how classification schemes and regulatory rules have limited understanding of their scope of effectiveness; and what changes are needed in research approaches to facilitate novel therapeutic discovery.