A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials

Abstract

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

The burden associated with, and management of, difficult-to-treat depression in patients under specialist psychiatric care in the United Kingdom

“…There is significant variation in the literature regarding the definition of TRD (Brown et al, 2019). A Delphi-method-based consensus on the definition of TRD for clinical trials (Sforzini et al, 2021) strongly supported the notion of two failed treatments as a relevant threshold. There was moderate consensus that these two treatments might include neurostimulation treatments such as ECT.…”

“…There was moderate consensus that these two treatments might include neurostimulation treatments such as ECT. The same guidelines recommend that failed courses of psychotherapy should not be considered as one of the previous treatments required to meet criteria for TRD, but with some disagreement between experts ( Sforzini et al, 2021 ). Our sample was identified in secondary, specialist, mental health care.…”

“…Nonetheless, previous studies using the same UK-CRIS system have demonstrated the feasibility of this approach ( Goodday et al, 2020 ; Kormilitzin et al, 2021 ; Vaci et al, 2020 ). Also, the inclusion of a review of clinical documentation in the assessment of the efficacy of antidepressant treatment trials has been highlighted as a recommendation for practice ( Sforzini et al, 2021 ). In interpreting the data extracted in an analysis of this type, one should be mindful that patterns and relative proportions are more meaningful than the precise absolute numerical values.…”

“…In addition, the concept of TRD does not address issues of lack of tolerability of treatment or the key issue of a non-sustained response/remission, the risk of which is known to be higher the more previous failed treatment trials a patient has had ( Rush et al, 2006 ). The first recommendation of a Delphi-method-based consensus guideline for the definition of TRD ( Sforzini et al, 2021 ) was the need for a ‘definition of TRD for clinical trials conducted for regulatory purposes’, highlighting the challenge arising from the lack of clear criteria. It has been proposed that a more heuristic conceptualisation is of ‘difficult-to-treat depression’ (DTD) based upon a clinically determined situation in which a patient is suffering from MDD that continues to be associated with a significant burden despite usual treatment interventions ( McAllister-Williams et al, 2020 ; Rush et al, 2019 ).…”

Sickness Behaviour and Depression: An Updated Model of Peripheral-Central Immunity Interactions

“…Treatment efficacy is quite variable and must be tailored to the tolerance of the treatment that also varies substantially (5). Frequently however, even with multiple medication exposures, pharmacological treatments fail to improve MDD symptoms with as many as one third of individuals not achieving full symptomatic remission (6), and even fewer meeting criteria for both symptomatic and functional remission (7,8).…”