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Recently, two synthetic analogs of the neurosteroid allopregnanolone\u2014brexanolone and zuranolone\u2014received approval in the United States for the treatment of postpartum depression (PPD) exhibiting a rapid, long\u2010lasting antidepressant effect through a novel mechanism of action. These developments mark a milestone in psychiatric research and advancement in available treatment options. In this review, we examine the role of neurosteroids in perinatal depression, with particular emphasis on their impact on network states and functional connectivity. We synthesize current clinical experience with brexanolone and zuranolone in the treatment of PPD, highlighting efficacy and practical considerations. Finally, we explore emerging precision medicine approaches that leverage the heterogeneity of clinical presentations and treatment responses in PPD to guide the development of targeted therapeutic strategies for this widely prevalent and debilitating condition.<\/jats:p>","DOI":"10.1111\/jne.70253","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:24:10Z","timestamp":1788409450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The neurosteroid paradigm in perinatal depression: From pathophysiology to precision therapeutics"],"prefix":"10.1111","volume":"38","author":[{"given":"Nevena V.","family":"Radonji\u0107","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Norton College of Medicine SUNY Upstate Medical University  Syracuse New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khatiya C.","family":"Moon","sequence":"additional","affiliation":[{"name":"Northwell Health  New Hyde Park New York USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Northwell Health  Manhasset New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina M.","family":"Deligiannidis","sequence":"additional","affiliation":[{"name":"Northwell Health  New Hyde Park New York USA"},{"name":"Institute of Behavioral Science, Feinstein Institutes for Medical Research, Northwell Health  Manhasset New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"Diagnostic and Statistical Manual of Mental Disorders","author":"APA","year":"2022"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000183597.31630.db"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010clinpsy\u2010050212\u2010185612"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00127\u2010022\u201002386\u20109"},{"key":"e_1_2_9_6_1","first-page":"119","volume-title":"AHRQ Evidence Report Summaries Rockville (MD): Agency for Healthcare Research and Quality (US); 1998\u20132005","author":"Gaynes BN","year":"2005"},{"issue":"5","key":"e_1_2_9_7_1","first-page":"849","article-title":"Pregnancy\u2010related deaths: data from maternal mortality review committees in 36 US states, 2017\u20102019","volume":"140","author":"Trost SL","year":"2022","journal-title":"Obstet Gynecol"},{"key":"e_1_2_9_8_1","unstructured":"FelkerA PatelR KotnisR KenyonS KnightM.Saving Lives Improving Mothers' Care Compiled Report\u2014Lessons Learned to Inform Maternity Care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2021\u201323. on behalf of MBRRACE\u2010UK.2025."},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/1745506519844044"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00737\u2010014\u20100445\u20104"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1017\/s0033291713001530"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2105\/ajph.2020.305619"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.15r10174"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgwh.2024.1428494"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.06.019"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(18)31551\u20104"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.20220785"},{"key":"e_1_2_9_18_1","unstructured":"MHRA.MHRA approves zuranolone to treat postnatal depression in adults following childbirth.https:\/\/www.gov.uk\/government\/news\/mhra\u2010approves\u2010zuranolone\u2010to\u2010treat\u2010postnatal\u2010depression\u2010in\u2010adults\u2010following\u2010childbirth"},{"key":"e_1_2_9_19_1","unstructured":"Commission E.Commission authorises medicine to treat postpartum depression. 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