Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression.

Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO's beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with (n = 9) or without (n = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, pnominal < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (GAD1), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism.

Evidence Guiding Withdrawal of Mechanical Ventilation at the End of Life: A Review.

OBJECTIVE: Distress at the end of life in the intensive care unit (ICU) is common. We reviewed the evidence guiding symptom assessment, withdrawal of mechanical ventilation (WMV) process, support for the ICU team, and symptom management among adults, and specifically older adults, at end of life in the ICU. SETTING AND DESIGN: Systematic search of published literature (January 1990-December 2021) pertaining to WMV at end of life among adults in the ICU setting using PubMed, Embase, and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. PARTICIPANTS: Adults (age 18 and over) undergoing WMV in the ICU. MEASUREMENTS: Study quality was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Out of 574 articles screened, 130 underwent full text review, and 74 were reviewed and assessed for quality. The highest quality studies pertained to use of validated symptom scales during WMV. Studies of the WMV process itself were generally lower quality. Support for the ICU team best occurs via structured communication and social supports. Dyspnea is the most distressing symptom, and while high quality evidence supports the use of opiates, there is limited evidence to guide implementation of their use for specific patients. CONCLUSION: High quality studies support some practices in palliative WMV, while gaps in evidence remain for the WMV process, supporting the ICU team, and medical management of distress. Future studies should rigorously compare WMV processes and symptom management to reduce distress at end of life.

Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression.

Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential affective response, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions mimicking pregnancy and parturition: supraphysiologic E2 + P-addback; supraphysiologic E2 + P-withdrawal; and no added E2 + P (Baseline). RNA-sequencing identified unique differentially expressed genes (DEGs) in all hormone conditions, but the majority tended to be downregulated in PPD and observed in E2 + P-addback. Two of these DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the 'Hippo' pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting innate differences in intracellular signaling in PPD. In certain hormone conditions, PPD LCLs displayed increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2α (the ultimate downstream target of IMPACT). Taken together, these transcriptomic data primarily implicate innately dysregulated cellular responses as potentially influencing mood and/or escalating PPD risk. Furthermore, the intrinsic downregulation of IMPACT's translation and WWTR1's transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.