PROJECT SUMMARY / ABSTRACT Unsuccessful regulation of affect and physiology (RAP) is central to many forms of psychopathology, including depression, one of the leading causes of disability worldwide. A core feature of major depressive disorder is persistent sadness, which often results from difficulty successfully regulating affect and physiology. Heterogeneity in the course of illness and response to treatment in depression is likely due to the presence of multiple phenotypes that confer risk via distinct mechanisms. Individuals with remitted depression (rMDD) appear to be less successful than controls on two distinct dimensions of regulation in everyday life: Perceived success – how successful explicit regulation is at improving affect; and Physiological success – the degree of parasympathetic augmentation following regulation attempts, primarily an implicit regulation process. Classifying individuals into subgroups (i.e., phenotypes) according to scores on each regulatory dimension can have clinical utility, providing distinct mechanism-based targets for remediation based on explicit and/or implicit regulation. Our approach involves three phases: First, we plan to characterize regulation phenotypes by screening young adults with rMDD (n=184) and healthy comparisons (n=68) based on our previously successful dimensional ambulatory assessment of RAP in everyday life. Second, participants will complete deep phenotyping in the lab to validate neural and physiological mechanisms underlying their phenotypic RAP classification. Third, we will examine the remediating effects of heart rate variability (HRV) biofeedback on proximal measures of RAP success in everyday life, particularly for subgroups who demonstrated unsuccessful RAP. By identifying and elucidating mechanisms of phenotypes based on ecologically-valid measures of RAP success, this study will help to parse the heterogeneity that exists within depression. Determining how HRV biofeedback impacts everyday regulation success for specific phenotypes can serve as an initial step toward guiding precision medicine. Thus, this project is highly responsive to NIMH’s strategic plan to identify when, how, and for whom to intervene.