Managing Treatment-Resistant Depression Road to Novel Therapeutics - Chapter 1: Defining treatment-resistant depression, difficult-to-treat depression, and staging treatment intensity

There is clear importance in being able to define patients with depression with poor outcomes to treatment so that factors underlying poor responses can be studied, as well as to facilitate treatment trials in this population. While there is general consensus that “treatment-resistant depression (TRD)” is defined as a situation where a patient with depression has failed to respond to two consecutive adequate trails of different antidepressants, there is a general lack of consensus with regard to the details of this. For example, it is unclear how long the trials should be, how a failure to respond should be define and measured, what dose of an antidepressant constitutes an adequate one, whether the drugs need to be from different classes (and how these are defined), and how to take into account psychotherapy and neurostimulatory treatments. There is also a lack of evidence of any biological difference between treatment responsive vs nonresponsive that can be used to aid differentiation. Nevertheless, the TRD concept remains important for research and regulatory purposes. An alternative concept of depression with poor outcomes, particularly for clinical settings, is of “difficult-to-treat depression (DTD).” It is argued that DTD has semantic advantages over TRD since it is less pejorative and more collaborative in tone. Conceptually, DTD emphasizes a chronic, rather than acute, illness model and recognizes that poor outcomes not only arise from nonresponse/remission but also being unable to sustain this, as well as intolerance of treatments. The DTD model encourages holistic individualized treatment, targeting tractable causes of poor outcome and maximizing quality of life.