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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: , Identifier: NCT03013400.

Original publication




Journal article


Psychopharmacology (Berl)

Publication Date



Add-on, Bipolar, Ebselen, Lithium mimetic, Mania, Randomised clinical trial, YMRS