{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:04:59Z","timestamp":1784286299959,"version":"3.55.0"},"reference-count":33,"publisher":"Royal College of Psychiatrists","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Br J Psychiatry"],"abstract":"<jats:sec id=\"S0007125026106898_as1\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Most antidepressants do not independently treat impaired cognition associated with major depressive disorder (MDD). Elevated brain cortisol levels are associated with both MDD and cognitive impairment. Emestedastat is a brain-penetrant, intracellular cortisol synthesis inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0007125026106898_as2\">\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The XanaCIDD trial aimed to determine whether emestedastat 10 mg could improve both cognitive impairment and depression in a population with persistent MDD and cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0007125026106898_as3\">\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 \u226517) and cognitive impairment (coding test \u22640.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks\u2019 blinded follow-up (week 10). The primary end-point was cognition (composite of attention\/working memory) at week 6. Depression end-points included Montgomery\u2013\u00c5sberg Depression Rating Scale (MADRS) and Patient Global Impression of Severity (PGI-S). Analyses used a mixed model for repeated measures (cognitive impairment and MADRS one-sided tests, others two-sided) and Cohen\u2019s\n                      <jats:italic>d<\/jats:italic>\n                      effect size. No adjustments were made for multiple comparisons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0007125026106898_as4\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 165 participants were enrolled and treated: 134 (81%) were on background antidepressants, 62% were female, mean prior number of MDD episodes was 10 and mean coding\n                      <jats:italic>z<\/jats:italic>\n                      -score was \u22121.47. There was no benefit on the primary cognitive end-point at week 6 (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2264 0.02). The trend towards benefit on the prespecified secondary depression end-point, MADRS, began at week 6 and was maximal at week 10 (2.7 points, Cohen\u2019s\n                      <jats:italic>d<\/jats:italic>\n                      0.43,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.12). Mild\u2013moderate transaminase elevations were seen in 10% of emestedastat participants (\u22642 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"S0007125026106898_as5\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>There was no benefit of emestedastat on the primary end-point of cognitive impairment and a large placebo effect, without correlation of cognitive impairment to depression changes or baseline characteristics. Trends towards potential antidepressant activity suggest that emestedastat may be a novel antidepressant worthy of further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1192\/bjp.2026.10689","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:16:30Z","timestamp":1784283390000},"page":"1-8","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":0,"title":["A Phase 2 randomised, double-blind, placebo-controlled trial of emestedastat in patients with major depressive disorder and cognitive impairment"],"prefix":"10.1192","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3249-5409","authenticated-orcid":false,"given":"Jack D.","family":"Taylor","sequence":"first","affiliation":[{"name":"Actinogen Medical"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Rolan","sequence":"additional","affiliation":[{"name":"Actinogen Medical"},{"name":"University of Adelaide Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Jaros","sequence":"additional","affiliation":[{"name":"Lotus Clinical Research LLC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Metis Cognition Ltd"},{"name":"Amsterdam UMC"},{"name":"King\u2019s College London Institute of Psychiatry Psychology & Neuroscience"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H.","family":"Ratcliffe","sequence":"additional","affiliation":[{"name":"St Pancras Clinical Research Ltd"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5554-6946","authenticated-orcid":false,"given":"Michael","family":"Berk","sequence":"additional","affiliation":[{"name":"Deakin University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana C.","family":"Hilt","sequence":"additional","affiliation":[{"name":"Actinogen Medical"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"170","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"S0007125026106898_ref10","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.732157"},{"key":"S0007125026106898_ref4","doi-asserted-by":"publisher","DOI":"10.1002\/da.20546"},{"key":"S0007125026106898_ref31","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g1888"},{"key":"S0007125026106898_ref33","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.14m09688"},{"key":"S0007125026106898_ref9","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2019.00974"},{"key":"S0007125026106898_ref24","unstructured":"24 Psychopharmacologic Drugs Advisory Committee (PDAC) Meeting. 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Published by Cambridge University Press on behalf of Royal College of Psychiatrists","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial licence (https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original article is properly cited. The written permission of Cambridge University Press or the rights holder(s) must be obtained prior to any commercial use.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}]}}