What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials.
OBJECTIVE
To summarize and discuss the conceptual and operational definitions of treatment resistant/refractory depression (TRD) by systematically reviewing randomized controlled trials (RCTs) on its somatic treatment.


METHODS
We searched the MEDLINE, Cochrane Library, PsycINFO, and EMBASE for potentially relevant RCTs on the somatic treatment of TRD published from January 1996 to June 2006.


METHODS
Studies were included if they: (a) enrolled patients at least 18 years old with a primary diagnosis of unipolar major depression considered resistant/refractory to treatment at baseline, (b) had a randomized design, (c) were published in peer-reviewed journals, and (d) were written in English. Trials that enrolled patients with secondary depression were excluded from our review. Finally, the bibliographies of relevant articles were hand-searched for additional references. In total, 233 full electronic references were retrieved, from which 47 meet the inclusion criteria.


METHODS
Through a standardized form, we collected data describing the diagnostic procedure, the terminology and definition of TRD employed, the methodology for assessing the adequacy of previous treatments (in terms of type of ascertainment, dose, and duration), and the minimum required depressive symptoms at baseline.


RESULTS
Overall, RCTs diverged regarding the majority of the conceptual and methodological issues involved in the ascertainment of TRD. For example, eleven terms were used to describe resistance/refractoriness in depression, and six different criteria were employed to define the categorical presence of TRD (ranging form non-response to one antidepressant to non-response to two or more antidepressants from different pharmacological classes). Regarding the evaluation of previous treatments, the majority of RCTs did not use systematic methods to gather data, and diverge substantially on the minimum acceptable medication doses and trial durations.


CONCLUSIONS
There is a clear need for an internationally shared framework of concepts and methods for the investigation of TRD that could reduce current idiosyncrasies and provide a reference system. Such a foundation is essential for the interpretation of research findings and for their translation to clinical practice.
Berlim
Marcelo T
MT
6875 LaSalle Blvd., Douglas Hospital Research Centre, Frank B. Common Pavilion, Rm. F-3125, Montréal, Québec, Canada H4H 1R3.
Turecki
Gustavo
G
D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004351:Drug Resistance; D006801:Humans; D016239:MEDLINE / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic; D013673:Technology Assessment, Biomedical
D000928:Antidepressive Agents