From Resistance to Redesign––The Emerging Logic of Hybrid Care in Treatment-Resistant Depression

Background/Objectives: Treatment-resistant depression (TRD) remains one of the most urgent unmet needs in psychiatry, while its therapeutic pipeline is evolving rapidly. To characterize current development trajectories, we conducted a registry-anchored mapping of interventional trials in adults with major depressive disorder and treatment resistance (MDD-TRD), with the aim of defining the distribution of intervention types, endpoint choices, and key design features across the active trial landscape. Methods: We sys-tematically searched ClinicalTrials.gov, the EU Clinical Trials Information System, and ISRCTN for interventional MDD-TRD trials registered up to September 18, 2025. After data cleaning and cross-registry deduplication, 237 unique trials were retained. Inter-ventions were categorized as pharmacological, device-based, biologic/novel, or digi-tal-combined. Primary endpoints were flagged as standard when they explicitly refer-enced the Montgomery–Åsberg Depression Rating Scale or Hamilton Depression Rating Scale. We also examined developmental phase, sample size, and recurrent methodo-logical features. Results: Digital or hybrid programs accounted for most trials (73.8%), followed by device-based neuromodulation studies (23.6%), pharmacological interven-tions (2.1%), and biologic/novel approaches (0.4%). Standard clinician-rated primary endpoints were used in 63.3% of studies. Trial development was concentrated in mid-phase designs, whereas sample sizes were generally modest (median 49; inter-quartile range, 19-87). Overall, the registered landscape suggested a shift away from novel molecules and toward digital-somatic hybrid models and precision neuromodu-lation. Across modalities, increasing attention was directed to durability of response, functioning, and patient-reported outcomes, with adaptive and enrichment-based designs appearing with greater frequency. Conclusions: The contemporary TRD trial ecosystem appears to be reorganizing around stratified, biomarker-informed, and multimodal care rather than conventional drug development alone. This registry-based mapping provides a near-real-time overview of the field and may support future harmonization of trial endpoints and design standards.