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

Perinatal depression affects 6.5-12.9% of mothers, with comorbid perinatal anxiety occurring in as many as 50% of cases. In low-income, minoritized women, rates of these perinatal affective disorders (PNADs) are even higher. It is important to further our understanding of PNADs to more efficaciously identify and treat women, especially in at-risk populations, while also considering the heterogeneity of symptoms within PNADs. The Research Domain Criteria (RDoC) framework is a tool for applying multi-level mechanistic approaches to mental health research across a variety of units of analysis. Neuroactive steroid metabolites of progesterone fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNADs. These neuroactive steroids alter the neural circuitry (i.e., inhibitory GABAergic potentiation) modulating certain RDoC phenotypes, namely potential threat, or responses to potentially aversive situations. The present study examined the relationship between neuroactive steroid metabolites of progesterone and PNADs (depression and anxiety) in early pregnancy, and explored the mediating effect of potential threat on this relationship through use of longitudinal self-report and physiologic measures. Data include neuroactive steroid quantification and self-reported depression, anxiety, and potential threat from 70 women at 2 visits (first and second trimester) in early pregnancy. A subset of participants (N=23) completed a physiologic acoustic startle task as a physiological index of potential threat and GABAA receptor sensitivity to neuroactive steroids. A greater increase in allopregnanolone levels and ratios to progesterone predicted greater increases in depression and anxiety, and a decrease in the acoustic startle response. Further, higher 1st trimester allopregnanolone predicted increased behavioral inhibition, which mediated an increase in depressive symptom severity, while higher 1st trimester pregnanolone predicted increased intolerance of uncertainty, mediating an increase in anxiety. Higher 1st trimester ratios of all steroids to progesterone predicted greater increase in the startle response. Findings suggest that potential threat is an important transdiagnostic symptom influenced by early pregnancy rise in neuroactive steroids, and that this mediates development of or worsening of depression and anxiety. This supports future work to assess potential therapeutics targeting potential threat and the neurosteroid system during pregnancy.