Treatment-resistant depression: time to rethink current definitions and clinical practice

The Legacy Framework of TRD Treatment-resistant depression (TRD) is a construct that was first introduced in the 1970s (1), and was further developed in subsequent decades through staging models such as those proposed by Thase and Rush (1997) and the Maudsley Staging Method (2009), offering useful frameworks that nonetheless failed to resolve persistent definitional heterogeneity (2). Despite nearly thirty years of scientific progress, continued reliance on conceptual models elaborated in an earlier phase of psychiatry limits the integration of contemporary evidence into both the definition and clinical management of TRD. The ongoing lack of consensus on what constitutes "treatment resistance" reveals underlying conceptual limitations (3); (4) and underscores the need for a critical re-evaluation of the construct in light of current evidence, together with the development of updated conceptual frameworks that integrate recent psychiatric advances and move toward a more unified and operational definition (4). The systematic review by Brown et al. (2019) exemplifies this definitional complexity, identifying as many as 155 distinct definitions of TRD across the literature (5). Such variability ranging from the failure of a single antidepressant to multiple unsuccessful trials across different pharmacological classes, undermines study comparability, generalisability of findings, and patient identification for advanced therapeutic strategies. Regulatory authorities have likewise adopted differing operational criteria, with direct implications for treatment access and the comparability of study data. The European Medicines Agency (EMA), in its Guideline on the Clinical Investigation of Medicinal Products in the Treatment of Depression (EMA/CHMP/185423/2010 Rev. 3,2025), drawing on the model proposed by Souery (1999), defines TRD as a lack of clinically meaningful improvement following two antidepressant trials from different pharmacological classes, each administered at an adequate dose and duration with documented treatment adherence (6). Unlike the quantitative symptom reduction thresholds derived from Delphi consensus methods (