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Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5\u2009mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4\/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo\/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [\u00b1SD] age: 24.1 [\u00b14.8] years, 15\u2009F) showed significantly elevated rCBF compared to HC (mean [\u00b1SD] age: 26.5 [\u00b15.1] years, 11\u2009F) in the hippocampus (\n                    <jats:italic>F<\/jats:italic>\n                    (1,41)\u2009=\u200924.7,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>FDR<\/jats:sub>\n                    \u2009&lt;\u20090.001) and across its subfields (all\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>FDR<\/jats:sub>\n                    \u2009&lt;\u20090.001). Following diazepam, rCBF in the hippocampus (and subfields, all\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>FDR<\/jats:sub>\n                    \u2009&lt;\u20090.001) was significantly reduced (\n                    <jats:italic>t<\/jats:italic>\n                    (69)\u2009=\u2009\u22125.1,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>FDR<\/jats:sub>\n                    \u2009&lt;\u20090.001) and normalized to HC levels (\n                    <jats:italic>F<\/jats:italic>\n                    (1,41)\u2009=\u20090.4,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>FDR<\/jats:sub>\n                    \u2009=\u20090.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.\n                  <\/jats:p>","DOI":"10.1038\/s41386-024-01864-9","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T14:02:13Z","timestamp":1713967333000},"page":"1448-1458","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis"],"prefix":"10.1038","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6582-2545","authenticated-orcid":false,"given":"Nicholas R.","family":"Livingston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6819-8090","authenticated-orcid":false,"given":"Amanda","family":"Kiemes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7766-1187","authenticated-orcid":false,"given":"Gabriel A.","family":"Devenyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Knight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina B.","family":"Lukow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke A.","family":"Jelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Dima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5401-8391","authenticated-orcid":false,"given":"Maria Antonietta","family":"Nettis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Casetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Agyekum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Zelaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"De Micheli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Fusar-Poli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1864-5504","authenticated-orcid":false,"given":"Anthony A.","family":"Grace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-1941","authenticated-orcid":false,"given":"Steve C. 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