Research challenges in chronic diseases: Difficult to treat depression

Abstract

Abstract Over a third of treatment-seeking outpatients with Major Depressive Disorder will not achieve or or sustain symptom remission despite multiple, well-delivered treatments. These patients experience prolonged suffering, chronically poor function and quality of life, and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of “difficult-to-treat depression” (DTD) aims to broaden our understanding and focus attention on the identification, evaluation, clinical management, treatment selection, and the diverse outcomes beyond symptoms that are critical to these patients. The DTD conceptualization calls for reconsidering the clinical research methods, study designs and tools that have been used to detect short-term therapeutic effects in treatment-responsive populations. This presentation reviews three essential challenges for clinical intervention research in DTD: 1) how to define and subtype this heterogeneous group of patients; 2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and 3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain. An evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and sub-typing DTD into more homogeneous groups. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on QoL or daily function. Trial methodology will also require modification as trials in DTD will likely be of longer duration to examine sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments. Keywords: DTD, TRD, Research, Design