Beyond DSM Categories: Criteria for Biologically Valid Disease Axes in Psychiatry.

Dimensional and transdiagnostic models have become central to contemporary efforts to move psychiatric nosology beyond DSM/ICD categories. This shift reflects persistent limitations of categorical syndromes as final biological targets, including within-diagnosis heterogeneity, cross-diagnostic comorbidity, developmental instability, and incomplete alignment with underlying mechanisms. This article examines a central unresolved problem in this transition: when, if ever, a descriptive or predictive psychiatric dimension can be interpreted as a candidate disease axis. We conducted a conceptual synthesis of major dimensional and transdiagnostic frameworks, including Research Domain Criteria (RDoC), Hierarchical Taxonomy of Psychopathology (HiTOP), the general psychopathology factor, cross-disorder genomic models, clinical staging approaches, and data-driven subtyping. The analysis separates three levels of inference that are often conflated in psychiatric research: descriptive structure, predictive utility, and disease-level biological validity. The synthesis identifies a recurrent inferential error in which reproducible factors, clusters, or classifiers are prematurely treated as evidence of disease architecture. Such constructs may describe real covariance patterns or improve prognostic prediction without establishing biological validity. We propose an eight-domain hierarchical framework for promotion to candidate disease-axis status, organized into four core gatekeepers-replication across cohorts, ascertainment, and methods, developmental coherence, incremental prognostic value beyond diagnosis and nonspecific severity, and discriminability from nonspecific severity-and four supporting/disciplining domains: cross-level convergence, mechanistic constraint, clinical leverage, and explicit falsifiability/boundary conditions. On this basis, middle-level transdiagnostic spectra and selected cross-disorder genomic liabilities appear more defensible as candidate disease axes than highly global or weakly specified constructs. Psychiatry was justified in turning toward dimensional models, but dimensionality alone does not confer biological validity. The key task is not to choose between categories and dimensions, but to define the evidential thresholds under which dimensional constructs warrant ontological promotion.