Therapeutic alternatives for difficult-to-treat depression: a narrative review of the state of the evidence.

Despite the large number of depressed patients who do not respond to first-line antidepressants, the evidence base of alternate strategies is quite thin. In this article, a simple 5-stage system for categorizing treatment-resistant depression (TRD) is described and the evidence pertaining to the major strategies currently utilized is summarized using four grades, ranging from D (case reports only) to A (multiple positive placebo-controlled trials). It is concluded that the level of evidence supporting many of the contemporary strategies used for TRD (eg, combinations of antidepressants and augmentation with medications such as pindolol, buspirone, or modafinil) is scanty at best. Even the fundamental question concerning "to augment or to switch" is not answerable with available data. It is noted that the best-documented treatments (ie, lithium augmentation, switching to a monoamine oxidase inhibitor, and electroconvulsive therapy) are among the least utilized. This state of affairs will improve with completion of the studies of Systematic Treatment Alternatives to Relieve Depression, a large multicenter study of difficult-to-treat depression funded by the National Institute of Mental Health. There is a need for greater collaboration among academicians and organizations, such as the American Psychiatric Association, the National Institute of Mental Health, and the pharmaceutical industry, to ensure that sufficient research is conducted so that clinician's choices for patients with TRD can be guided by empirical evidence.