664. From criteria to cure: definitions, immune targets, and adaptive treatment-trials in treatment-resistant depression

Abstract

Abstract Background Despite the availability of multiple effective treatments for major depressive disorder (MDD), inadequate treatment response remains common in clinical practice. Key barriers limiting progress in this area include inconsistent definitions of non-response and insufficient consideration of biological heterogeneity in clinical research. The absence of operationalised criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) reduces comparability across studies and limits the generalisability of findings to real-world populations. In parallel, the lack of biological characterisation addressing the heterogeneity of MDD continues to hinder the development of personalised and mechanism-based treatment approaches (Amasi-Hartoonian et al., J Affect Disord, 2022). Aims & Objectives This presentation aims to address the challenge of defining non-response in MDD by presenting recent consensus-based operational criteria for TRD and PRD developed for use in clinical trials. It further aims to review emerging evidence on biological mechanisms associated with non-response, with a particular focus on immune dysregulation and its potential for identifying clinically relevant patient subgroups and novel therapeutic targets. Finally, the presentation outlines future research directions, including separate initiatives focused on biological stratification and on innovative clinical trial designs, to support the development of precision psychiatry approaches. Method Multiple complementary research approaches are presented. First, a Delphi-method-based consensus guideline involving international experts, regulators, industry representatives, and a patient representative was used to establish operational criteria for TRD and PRD in clinical trial settings. Second, biological mechanisms underpinning non-response are examined through transcriptomic analyses and broader immunopsychiatry research, including evidence from clinical trials targeting inflammation in non-responsive depression. Third, ongoing research initiatives are reviewed: one focusing on immune-based patient stratification to inform personalised treatment strategies, and another employing adaptive, multi-arm platform trial designs to improve efficiency in testing novel interventions in TRD and PRD. Results The Delphi process provides clear, operational definitions for TRD and PRD, enabling more consistent patient selection, improved cross-study comparability, and alignment with regulatory expectations (Sforzini et al., Mol Psychiatry, 2022). Immunopsychiatric and transcriptomic findings suggest that immune dysregulation characterises specific subgroups of patients with non-responsive depression, with inflammation-related pathways emerging as potential therapeutic targets (Sforzini et al., Mol Psychiatry, 2024). Evidence from stratified analyses indicates that treatment effects of anti-inflammatory interventions may depend on baseline immune activation (Sforzini et al., J Affect Disord, 2025), underscoring the need for biologically informed patient stratification (Worrell et al., Lancet Psychiatry, 2025). In parallel, adaptive platform trial designs demonstrate feasibility for accelerating clinical research in TRD and PRD using standardised definitions within a single master protocol. Discussion & Conclusions These findings highlight the need to move beyond one-size-fits-all approaches in depression research. Establishing standardised definitions of non-response represents a critical first step toward improving the quality and interpretability of clinical trials. In parallel, immune-based biological stratification offers a promising pathway for identifying more homogeneous subgroups and informing targeted interventions. Innovative trial designs, such as adaptive platform trials, can further enhance efficiency and scalability. Together, these complementary strategies provide a foundation for advancing precision psychiatry in MDD and improving outcomes for patients who do not respond to conventional treatments (Miller et al., Brain Behav Immun, 2025).