An RDoC Approach to Perinatal Affective Disorders: The Role of Neuroactive Steroids and Potential Threat

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PROJECT SUMMARY / ABSTRACT Perinatal depression (PND) affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety (PNA) occurring in as many as 50% of cases. In low-income women of color, rates of these perinatal affective disorders (PNAD) are even higher. PNAD are associated with adverse effects on both maternal and infant health and can contribute to pre-term birth and low birth weight. It is important to further our understanding of PNAD to more efficaciously identify and treat women, especially in at-risk populations. We must also address the considerable heterogeneity of mental health symptoms and recognize the potential variations in pathogenesis and symptom profiles from patient to patient. To our knowledge, despite this heterogeneity, studies to date have investigated biomarkers of PNAD almost exclusively in relation to diagnoses rather than symptom phenotypes. The Research Domain Criteria (RDoC) framework is a tool for applying new, multi-level mechanistic investigational approaches to mental health, integrating self-report, behavioral, physiological and biological measures. RDoC tools have not yet been applied to identify transdiagnostic phenotypes of PNAD and their neural basis. Neuroactive steroid metabolites of progesterone fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNAD. These neuroactive steroids alter the neural circuitry (i.e., inhibitory GABAA receptor) modulating certain RDoC phenotypes, particularly potential threat, or responses to potentially aversive situations. Preliminary data show potential threat to be an RDoC phenotype common in PNAD, and neuroactive steroids to relate to PNAD. The next step is to link potential threat directly to neuroactive steroids, and to extend research to other metabolites of progesterone, particularly early in pregnancy when rates of PNAD are highest in women of color. The research goal of this proposal is to examine neuroactive steroid synthesis in relation to self-report and physiological measures of potential threat as well as PNAD symptoms in early pregnancy in low-income women of color. The specific aims are to (1) investigate acute increases in NAS synthesis as a mechanism of potential threat in early pregnancy; (2) investigate the association of NAS synthesis with depression and anxiety symptoms in early pregnancy, and whether potential threat mediates these associations; and (3) investigate the acoustic startle response as a physiological index of potential threat and GABAA receptor sensitivity to NAS during pregnancy. The training goals are to (1) develop a theoretical understanding of the RDoC framework and apply the framework to the study of perinatal mental health phenotypes; (2) acquire training in processing and analysis of neuroactive steroids, and gain knowledge of their association with PNAD; and (3) develop a detailed understanding of female reproductive physiology and endocrinology, and relate this to perinatal affective disorders. Ultimately, this training will allow the applicant to advance towards a goal of becoming an independent academic researcher studying the pathogenesis and heterogeneity of perinatal mental health in low income, minority patient populations.