Reproductive Endocrine Related Mood Disorders-Differential Sensitivity

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This report includes work arising from the following clinical protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481. The studies conducted within this project are relevant to our understanding of womens behavioral health, sex differences in psychiatric illness and the course of affective disorders in general. The innovation in our work is both conceptual as well as applied. In the past, RMDs were considered to be hormone excess or deficiency states, prompting treatments to correct these inferred hormonal imbalances. We address critical mechanistic questions about the role of reproductive hormones on brain function and behavior in RMDs. We employ steroid receptor modulators to isolate and characterize the effects of specific steroids on behavior in both women with RMDs and well-characterized asymptomatic controls. These clinical studies have demonstrated that a change in steroid hormone secretion induces affective symptoms in most women clinically diagnosed with RMDs, but the identical hormonal intervention has no effect on mood/behavior in asymptomatic controls. Thus, our work has reframed the understanding of these conditions from hormonal excess or deficiency states to that of ovarian steroid-sensitive behavioral states. We also employ both multimodal neuroimaging studies and in vitro cellular models to investigate the physiologic basis of the hormone sensitive phenotype in RMDs. We have characterized neuronal hubs that are differentially regulated by ovarian steroids in women with RMDs, developed a steroid metabolomics platform to examine the steroid metabolome in PMDD, demonstrated an impact of genotypic variation in steroid-regulated genes on the central nervous system (CNS) response to steroids (in a brain region-specific manner), and identified underlying cellular mechanisms for the alterations in steroid signaling in both PMDD and PPD (the mechanisms underlying several of which are being actively pursued). These findings are unique and serve to inform our understanding of the pathophysiology of these conditions and their potential comorbidities, their clinical management and use of hormone therapies. Finally, having developed and tested these methods in women with RMDs, we will employ these techniques in our new studies of postpartum psychosis a condition potentially lethal to both mother and child. Findings to date include: 1) the differential affective and behavioral response to normal physiologic events in women with PMDD compared with control women a behavioral phenotype in which we have explored the underlying biologic risks. We now have replicated these findings which were originally reported in a relatively small sample (i.e., ten women with PMDD and fifteen controls) now in much larger samples of women with PMDD (n=34) and controls (n=76). We found the identical phenomenon of mood destabilization after exposure to physiologic levels of either estradiol or progesterone in women with PMDD, but no effect of hormonal exposure in asymptomatic control women. Interestingly, the symptom of irritabilitys recurrence in PMDD was more related to progesterone exposure (and therefore neurosteroid) than to estradiol exposure. Additionally, physical symptoms of breast pain, bloating and food cravings showed a similar pattern of hormone-triggered recurrence in PMDD but with more specificity (e.g., breast pain only appeared after exposure to estradiol). 2) We employ a machine learning platform in a large sample of over 800 women (women who met DSM criteria for PMDD, asymptomatic controls and women who presented with PMDD but who did not meet research criteria for PMDD) who completed daily symptom ratings of sadness, anxiety and irritability across at least two menstrual cycles. We will examine several questions in this data set including the specificity of the symptom of irritability in PMDD, the clinical characteristics associated with PMDD (versus those who do not meet criteria for PMDD) and whether there are distinct patterns of symptom expression that define specific phenotypes of PMDD that will be employed with other ongoing studies (e.g., development of polygenic scores) to better characterize this condition. 3) In collaboration with Dr. David Goldman at NIAAA, we developed lymphoblastoid cell lines (LCLs) and human induced-pluripotent cell lines (h-IPSCs) from women with and without RMDs (i.e., women with PMDD, PPD, PPP and perimenopausal depression PMD). In LCLs from women with and without PPD, we observed that PPD LCLs had an intrinsic downregulation of transcript expression, with the greatest disparity between PPD cases and controls in differentially expressed genes during in vitro exposure to supraphysiologic levels of estradiol and progesterone (mimicking exposures during pregnancy). The top genes significantly decreased in PPD, (IMPACT, a translational regulator of cellular stress conditions, and WWTR1, a homeostatic mediator of transcription) suggest novel possible molecular targets underlying in vivo findings such as increased DNA methylation and desensitization of the glucocorticoid system in women who develop PPD compared to controls. Additionally, given the documented benefits of brexanolone (allopregnanolone ALLO) in PPD we examined the effects of ALLO on gene expression in cell lines from PPD and controls. In this study, gene expression in LCLs were studied after 60-hours of ALLO exposure. The major finding was that in LCLs from women with PPD (compared with their baseline expression), ALLO induced 2 fold fewer differentially expressed genes compared with gene expression within LCLs from matched controls. This suggests ALLO's potential to induce divergent cellular responses depending upon genetic (or diagnostic) background. These finding are currently being explored in ongoing studies examining the molecular and transcriptomic consequences of ALLO signaling within the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) in PPD, and which specific cell types are involved in this signaling (by employing single nucleus sequencing procedures). Finally, we explore how these changes in gene expression differ across species using transgenic mouse models of PPD and patient-derived LCL models for PPD and controls. We also are examining characteristics of the phenotype of differential ovarian hormone sensitivity across all RMDs, how genes and transcripts compare across disorders, and to non-endocrine related mood disorders such as depression. We are currently managing the inventory, organization, and development of a major genotyping project involving DNA samples and cell lines spanning 30 years across multiple RMDs - some 500 samples have been identified and physically located, with over 150 of these now genotyped utilizing the global diversity array, a chip with over 1.8 million SNPs of interest. These SNPs will be used to calculate polygenic scores for multiple phenotypes of interest. Finally, we have collected Ampliseq RNA-seq data on PMDD, PMD, PPD, and PPP at baseline, and we are currently devising an analysis pipeline to assess the intrinsic similarities and differences across these disorders and compared to controls.