Mapping depression rating scale phenotypes onto research domain criteria (RDoC) to inform biological research in mood disorders

Background: Substantial research progress can be achieved if available clinical datasets can be mapped to the National Institute of Mental Health Research-Domain-Criteria (RDoC) constructs. This mapping would allow investigators to both explore more narrowly defined clinical phenotypes and the relationship of these phenotypes to biological markers and clinical outcomes approximating RDoC criteria. Methods: Using expert review and consensus, we defined four major depression phenotypes based on specific RDoC constructs. Having matched these constructs to individual items from the Hamilton Depression Rating Scale and Quick Inventory of Depressive Symptomatology, we identified subjects meeting criteria for each of these phenotypes from two large clinical trials of patients treated for major depression. In a post hoc analysis, we evaluated the overall treatment response based on the phenotypes: Core Depression (CD), Anxiety (ANX), and Neurovegetative Symptoms of Melancholia (NVSM) and Atypical Depression (NVSAD). Results: The phenotypes were prevalent (range 10.5-52.4%, 50% reduction range 51.9-82.9%) and tracked with overall treatment response. Although the CD phenotype was associated with lower rates of remission in both cohorts, this was mainly driven by baseline symptom severity. However, when controlling for baseline severity, patients with the ANX phenotype had a significantly lower rate of remission. Limitations: The lack of replication between the studies of the phenotypes' treatment prediction value reflects important variability across studies that may limit generalizability. Conclusion: Further work evaluating biological markers associated with these phenotypes is needed for further RDoC concept development.