The relevance of phenotypic definition in treatment resistant forms of major depressive disorder: a narrative review.

Treatment-resistant depression (TRD) represents a major clinical and public health challenge contributing disproportionately to disability, healthcare utilisation, and societal costs. Progress in the field may be hindered by substantial heterogeneity in TRD phenotypic definitions and inconsistencies in their operationalisation across research and clinical settings. In this narrative review, we provide an updated overview of TRD research, focusing on limitations of current phenotypic frameworks, key sources of heterogeneity, and emerging biologically informed predictive approaches. We examine how variability in clinical assessment, comorbidities, treatment adherence, and adequacy of therapeutic trials may contribute to pseudo-resistance and consequent phenotypic instability, given that current TRD definitions largely rely on the number of failed antidepressant trials. Evidence on genetic, inflammatory, cognitive, and personality correlates of TRD is also summarised, highlighting both promising signals and persisting gaps. In addition, we discuss the potential role of measurement-based care and algorithm-guided treatment strategies in improving TRD identification and management. Overall, convergence toward more standardised TRD phenotyping-particularly through systematic assessment of adherence and symptom dimensions-appears essential to enhance ecological validity, support precision psychiatry, and advance translational research.