Defining treatment-resistant depression: a comprehensive review of the literature

Ann Clin Psychiatry. 2014 Aug;26(3):222-32.


Background: Despite the common occurrence and debilitating nature of treatment-resistant depression (TRD), currently there is no universally accepted definition for TRD. This review summarizes the different methods used to define TRD, and provides an overview of the TRD literature.

Methods: PsycInfo, Medline, and Ovid were searched to identify relevant articles published in peer-reviewed journals. A combination and/or variation of the following keywords were searched: treatment resistant, treatment refractory, depression, defining, staging, and modeling. Identified articles provided a description of the methods utilized for defining and/or measuring TRD, prevalence and impact of TRD, risk factors for TRD, and/or factors that contribute to the misclassification of non-TRD patients.

Results: Multiple methods for defining/measuring TRD have been proposed; however, variability in these methods has limited the comparability between TRD studies. Although various risk factors for TRD have been suggested, few have been consistently supported. The misclassification of non-TRD patients as having TRD is related to various clinical and treatment-related factors.

Conclusions: Adopting a universal standard definition for TRD is necessary to reduce the variability in how TRD is defined, and the misclassification of non-TRD patients. A universal definition would benefit clinical and research settings by allowing data to be easily compared across these settings.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major / classification
  • Depressive Disorder, Major / diagnosis*
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Treatment-Resistant / classification
  • Depressive Disorder, Treatment-Resistant / diagnosis*
  • Depressive Disorder, Treatment-Resistant / drug therapy
  • Diagnostic Errors*
  • Humans
  • Severity of Illness Index


  • Antidepressive Agents