Table 1.
Main consensus recommendations on TRD/PRD regulatory clinical trials.
| Level of consensus– Strong | % of agreement | |
| Recommendations which can be implemented within current practice | ||
| TRD and PRD definitions | ||
| 1 | A definition of TRD for clinical trials conducted for regulatory purposes is necessary. | 98% |
| Previous antidepressant treatments | ||
| 3 | TRD should be defined after a minimum of two failed treatments with <25% of improvement with adequate dosing and duration. | 96% |
| Type of medications | ||
| 10 | Discontinuation of treatment before the completion of the fourth week, without clear evidence of lack of response, should not be considered as a treatment failure for the purpose of establishing TRD/PRD. | 96% |
| Exclusion from TRD/PRD studies | ||
| 12 | A previous structured psychotherapy failing to improve MDD symptoms is not an exclusion criterion. | 100% |
| Clinical presentation | ||
| 15 | All specifiers of depression (melancholic, atypical, anxious, psychotic, mixed) should be considered within the TRD/PRD definition, except for bipolar depression. | 95% |
| Recommendations which can be implemented in future research | ||
| 21 | Future research should recognize and target different clinical phenotypes of TRD (and PRD) underpinned by a specific biological mechanism. | 100% |
| 22 | For future research, diagnostic and history-taking instruments should be implemented in clinical cohorts and electronic health records, to allow a reliable, comprehensive, and multidimensional evaluation of people with lived experience (PWLE). | 100% |
| 24 | Preferences, perspectives, and reported outcomes of PWLE should be included in future TRD (and PRD) diagnostic tools and outcome measures. | 100% |
| Level of consensus – Moderate | ||
| Recommendations which can be implemented within current practice | ||
| TRD and PRD definitions | ||
| 2 | It is important to distinguish between TRD and PRD for randomized clinical trials for new treatments. | 85% |
| Previous antidepressant treatments | ||
| 4 | PRD can be defined even after a single treatment (improvement 25 to <50%) with adequate dosing and duration. | 76% |
| 6 | It is possible to assess ineffective past/current antidepressant treatment attempts, but only if properly documented, that is, based not only on subjective recollection or standardised instruments to assess psychiatric history and previous treatments (see below), but also on clinical documentation. | 75% |
| Type of medications | ||
| 7 | To define TRD, the two antidepressant treatment failures should consist of two established (licensed) medications for MDD of different mechanisms of action. | 75% |
| 8 | A failed course of psychotherapy should not be included as one of the previous treatments required for the definition of TRD/PRD. | 78% |
| 9 | The criteria of ‘adequate dose and duration’ is the minimal effective dosage, that is, the minimal approved dosage, administered for at least four weeks. | 74% |
| Exclusion from TRD/PRD studies | ||
| 11 | Multiple-drug resistant individuals, and individuals in whom augmentation strategies failed to improve/eliminate MDD symptoms should not be excluded from TRD/PRD studies. | 93% |
| 13 | Individuals with MDD in whom deep brain stimulation (DBS) and vagus nerve stimulation (VNS) failed to improve/eliminate MDD symptoms should be excluded from TRD/PRD clinical studies. | 62% |
| 14 | Individuals with MDD in whom other non-continuous/non-invasive brain stimulation interventions, such as electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS), failed to improve/eliminate MDD symptoms should not be excluded. | 88% |
| Clinical presentation | ||
| 16 | Comorbid personality disorders or other mental disorders should be excluded from TRD/PRD studies only when their onset is properly documented as independent and antecedent to the MDD diagnosis. | 79% |
| 17 | Individuals with a severe substance use disorder not currently in remission should be excluded from TRD/PRD studies, independently from the onset; in contrast, individuals with comorbid substance use disorder that is active and mild/moderate should be excluded from TRD/PRD studies only when the onset is properly documented as independent and antecedent to the MDD diagnosis. | 83% |
| Diagnostic tools and measures of outcome | ||
| 18 | Maudsley Staging Model is the preferred instrument to assess TRD/PRD status. | 69% |
| 19 | Clinician administered MADRS10 is the preferred outcome instrument to assess treatment response (and remission), together with patient-reported QIDS-SR. |
MADRS = 85% QIDS-SR = 81% |
| 20 | Criteria for remission, response, and partial response should not be relaxed in regulatory clinical trials for TRD/PRD, and shorter versions of the traditional scales, such as the HAM-D6 and the MADRS6, should not be preferred to full scales. | 92% |
| Recommendations which can be implemented in future research | ||
| 23 | Currently, no biomarker has been validated in clinical practice or in clinical trials to identify people with TRD (and PRD), or to further stratify them; however, collection of biological samples for subsequent subgroup or stratified analyses is recommended. | 91% |
| 25 | The usefulness of adherence assessment using blood levels or other methods (also in a run-in period) should be assessed through research, before deciding whether it should be implemented in future clinical trials. | 92% |
| Level of consensus – Weak | ||
| Recommendations which can be implemented within current practice | ||
| Previous antidepressant treatments | ||
| 5 | The definition of TRD should include two treatment failures both within the current episode, and the definition of PRD should include partial response to at least one treatment within the current episode; moreover, for long current episodes, only treatment failures within the last two years should be considered. | 51% |