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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,5]]},"abstract":"<jats:p>Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and\/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.<\/jats:p>","DOI":"10.1073\/pnas.2305776120","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T15:22:27Z","timestamp":1701098547000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":28,"title":["Transcriptional signatures of early-life stress and antidepressant treatment efficacy"],"prefix":"10.1073","volume":"120","author":[{"given":"Sero Toriano","family":"Parel","sequence":"first","affiliation":[{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon N.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy J.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia C.","family":"Timmermans","sequence":"additional","affiliation":[{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Fiori","sequence":"additional","affiliation":[{"name":"Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-2736","authenticated-orcid":false,"given":"Gustavo","family":"Turecki","sequence":"additional","affiliation":[{"name":"Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine Jensen","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2017.08.019"},{"key":"e_1_3_4_2_2","first-page":"394283","article-title":"An overview of depression among transgender women","volume":"2014","author":"Hoffman B.","year":"2014","unstructured":"B. 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Balouek Reactivation of early-life stress-sensitive neuronal ensembles contributes to lifelong stress hypersensitivity. J. Neurosci. 43 5996\u20136009 (2023).","DOI":"10.1523\/JNEUROSCI.0016-23.2023"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","unstructured":"H. Kronman Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat. Neurosci. 25 667\u2013676 (2021) 10.1038\/s41593-021-00814-8.","DOI":"10.1038\/s41593-021-00814-8"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.12.010"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","unstructured":"S.-C. Fuh L. M. Fiori G. Turecki C. Nagy Y. Li Multi-omic modeling of antidepressant response implicates dynamic immune and inflammatory changes in individuals who respond to treatment. 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Wu , clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov. J. 2, 100141. (2021).","journal-title":"Innov. 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