A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as
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ORIGINAL INVESTIGATION
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 Ann L Sharpley 1,2 & Clare Williams 1,2 & Adele A Holder 1,2 & Beata R Godlewska 1,2 Milensu Shanyinde 3 & Orla MacDonald 2 & Philip J Cowen 1,2
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Nisha Singh 1
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Received: 29 June 2020 / Accepted: 26 August 2020 # The Author(s) 2020
Abstract Rationale Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. Objectives 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. Methods 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 (n = 68) aged 18–70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. Results Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, − 1.71 (− 5.34 to 1.91), p = 0.35) and ASRM (− 1.36 (− 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, − 0.58 (− 1.14 to − 0.03), p = 0.04). 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. Conclusions Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen’s superior tolerance and safety could make it a useful alternative to lithium. Trial registration Trial Registry: www.clinicaltrials.gov, Identifier: NCT03013400. Keywords Ebselen . Randomised clinical trial . Bipolar . Mania . Add-on . YMRS . Lithium mimetic
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-020-05654-1) contains supplementary material, which is available to authorized users. * Philip J Cowen [email protected] 1
Neurosciences Building, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK
2
Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
3
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxfor
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