Transdiagnostic, dimensional frameworks such as the Research Domain Criteria (RDoC) are increasingly regarded as promising vehicles for precision neuropsychiatric drug development, yet no treatment has been approved that was explicitly developed according to such principles. This work, conducted under the aegis of the European College of Neuropsychopharmacology Thematic Working Group on Clinical Outcomes in Early-Phase Clinical Trials, synthesises seven structured multidisciplinary expert meetings supported by a narrative literature review to delineate opportunities and barriers for implementing RDoC in early-phase clinical development. We identify four key operational domains that condition the success of RDoC-aligned programmes: (1) terminology clarity and working definitions for RDoC-aligned trials and target constructs; (2) construct-enriched population selection methodologies; (3) selection, development or modification of construct-aligned clinical outcome assessments that are fit-for-purpose in transdiagnostic research settings; and (4) navigation of regulatory frameworks that remain anchored in categorical diagnoses. Through selected illustrative cases—most notably the aticaprant development program targeting anhedonia in mood and anxiety disorders—we demonstrate how early phase RDoC-aligned trial designs can be compromised at the pivotal stage by the absence of validated endpoints and regulatory constraints on labelling. On this basis, we propose pragmatic recommendations, including consensus-based definitions, registry tagging of RDoC-aligned trials, data-driven biomarker-based transdiagnostic enrichment strategies (i.e., biotyping), and early, iterative engagement with regulators and health technology assessment agencies. Systematic attention to these domains is required for enabling the development of neurobiologically informed treatments to the right patients at the right time using the RDoC framework. Suggested key operational areas for the application of the Research Domain Criteria (RDoC) in early-phase clinical development of transdiagnostic neurotherapeutics. • Terminological standards for RDoC-aligned trials are needed for transparency, harmonization, and evidence synthesis. • Regulatory expectations for diagnosis-anchored labels and qualified endpoints are a key bottleneck limiting translation of RDoC principles in clinical development. • Data-driven biomarker-based subgrouping of study sample represents a promising construct-valid enrichment strategy in RDoC-aligned trials. • Fit-for-purpose construct-aligned COA instruments are essential to bridge between mechanistic signals and clinical benefits. • Initial anchoring of indications to categorical diagnoses and regulatory engagement are critical to secure acceptance of RDoC-aligned methodologies.
Magaraggia et al. (2026) studied this question.