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Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Objectives<\/jats:title>\n<jats:p>To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In\/outpatients (<jats:italic>n<\/jats:italic>\u2009=\u200968) aged 18\u201370, experiencing mania or hypomania, were assigned to 3\u00a0weeks ebselen (600\u00a0mg bd) (<jats:italic>n<\/jats:italic>\u2009=\u200933) or placebo (<jats:italic>n<\/jats:italic>\u2009=\u200935). Participants received usual clinical care and psychotropic medication.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, \u2212\u20091.71 (\u2212\u20095.34 to 1.91), <jats:italic>p<\/jats:italic>\u00a0=\u20090.35) and ASRM (\u2212\u20091.36 (\u2212\u20093.75 to 1.17), <jats:italic>p<\/jats:italic>\u00a0=\u20090.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, \u2212\u20090.58 (\u2212\u20091.14 to \u2212\u20090.03), <jats:italic>p<\/jats:italic>\u00a0=\u20090.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen\u2019s superior tolerance and safety could make it a useful alternative to lithium.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p>Trial Registry: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">www.clinicaltrials.gov<\/jats:ext-link>, Identifier: NCT03013400.<\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s00213-020-05654-1","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T12:53:09Z","timestamp":1599742389000},"page":"3773-3782","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania"],"prefix":"10.1007","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0623-1067","authenticated-orcid":false,"given":"Ann L","family":"Sharpley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele A","family":"Holder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5973-3765","authenticated-orcid":false,"given":"Beata R","family":"Godlewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1312-688X","authenticated-orcid":false,"given":"Nisha","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milensu","family":"Shanyinde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-6138","authenticated-orcid":false,"given":"Philip J","family":"Cowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,9]]},"reference":[{"key":"5654_CR1","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1042\/BST0371121","volume":"37","author":"G Agam","year":"2009","unstructured":"Agam G, Bersudsky Y, Berry GT, Moechars D, Lavi-Avnon Y, Belmaker RH (2009) Knockout mice in understanding the mechanism of action of lithium. 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