Hierarchical Inflammatory Phenotypes of Depression Incorporating a Diverse Array of Immune Proteins: A Pre-Registered Report

Background: The foundation of precision psychiatry is to clearly link mechanisms to specific levels of psychopathology (e.g., syndromes vs. symptoms). A critical obstacle to this goal is that most biological psychiatry research has failed to consider that key mechanisms such as inflammation may be simultaneously and uniquely associated psychopathology at multiple levels of measurement (e.g., syndromes and symptoms) in a hierarchical phenotype. Method: We conducted a pre-registered study that replicates and extends prior work on the hierarchical inflammatory phenotyping of depression using more comprehensive assessments of inflammation and depression in 2,055 adults (54.6% female, Mage = 55.4 years, 10.4-17.4% clinically elevated depression symptoms). Results: Controlling for sex, age, and disease burden, and using FDR-corrected p-values, moderated nonlinear factor analysis models higher inflammation was associated with higher latent depression, poor appetite, inability to “shake the blues”, greater perceived effort, increased feelings of failure, and (surprisingly, in one model) decreased sadness. Results differed by inflammatory variable, underscoring the need for diverse immune assessment in immunopsychiatry. Conclusions: Clinically, these results underscore the need to use approaches that can identify which mechanisms are associated with psychopathology at different levels of a diagnostic hierarchy. Further, different inflammatory processes likely have different psychological outputs—highlighting the need for more diversified immune assessment. Combined, they characterize more specific inflammation—depression pathways, laying the groundwork for precision immunopsychiatry.