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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.

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.

SUBMITTER: Sharpley AL

PROVIDER: S-EPMC7683468 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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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.

Sharpley Ann L AL Williams Clare C Holder Adele A AA Godlewska Beata R BR Singh Nisha N Shanyinde Milensu M MacDonald Orla O Cowen Philip J PJ

Psychopharmacology 20200909 12

<h4>Rationale</h4>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.<h4>Objectives</h4>To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and t ...[more]

PMID: 32909076

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Project description:Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ≥20, and score ≥4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add-on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.

Project description:BackgroundPediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder.MethodsWe conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression.ResultsThis study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint.ConclusionsThese pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample.Trial registrationClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.

Project description:ImportanceMania/hypomania is the pathognomonic feature of bipolar disorder (BD). Established, reliable neural markers denoting mania/hypomania risk to help with early risk detection and diagnosis and guide the targeting of pathophysiologically informed interventions are lacking.ObjectiveTo identify patterns of neural responses associated with lifetime mania/hypomania risk, the specificity of such neural responses to mania/hypomania risk vs depression risk, and the extent of replication of findings in 2 independent test samples.Design, setting, and participantsThis cross-sectional study included 3 independent samples of young adults aged 18 to 30 years without BD or active substance use disorder within the past 3 months who were recruited from the community through advertising. Of 603 approached, 299 were ultimately included and underwent functional magnetic resonance imaging at the University of Pittsburgh, Pittsburgh, Pennsylvania, from July 2014 to May 2023.Main outcomes and measuresActivity and functional connectivity to approach-related emotions were examined using a region-of-interest mask supporting emotion processing and emotional regulation. The Mood Spectrum Self-Report assessed lifetime mania/hypomania risk and depression risk. In the discovery sample, elastic net regression models identified neural variables associated with mania/hypomania and depression risk; multivariable regression models identified the extent to which selected variables were significantly associated with each risk measure. Multivariable regression models then determined whether associations in the discovery sample replicated in both test samples.ResultsA total of 299 participants were included. The discovery sample included 114 individuals (mean [SD] age, 21.60 [1.91] years; 80 female and 34 male); test sample 1, 103 individuals (mean [SD] age, 21.57 [2.09] years; 30 male and 73 female); and test sample 2, 82 individuals (mean [SD] age, 23.43 [2.86] years; 48 female, 29 male, and 5 nonbinary). Associations between neuroimaging variables and Mood Spectrum Self-Report measures were consistent across all 3 samples. Bilateral amygdala-left amygdala functional connectivity and bilateral ventrolateral prefrontal cortex-right dorsolateral prefrontal cortex functional connectivity were positively associated with mania/hypomania risk: discovery omnibus χ2 = 1671.7 (P < .001); test sample 1 omnibus χ2 = 1790.6 (P < .001); test sample 2 omnibus χ2 = 632.7 (P < .001). Bilateral amygdala-left amygdala functional connectivity and right caudate activity were positively associated and negatively associated with depression risk, respectively: discovery omnibus χ2 = 2566.2 (P < .001); test sample 1 omnibus χ2 = 2935.9 (P < .001); test sample 2 omnibus χ2 = 1004.5 (P < .001).Conclusions and relevanceIn this study of young adults, greater interamygdala functional connectivity was associated with greater risk of both mania/hypomania and depression. By contrast, greater functional connectivity between ventral attention or salience and central executive networks and greater caudate deactivation were reliably associated with greater risk of mania/hypomania and depression, respectively. These replicated findings indicate promising neural markers distinguishing mania/hypomania-specific risk from depression-specific risk and may provide neural targets to guide and monitor interventions for mania/hypomania and depression in at-risk individuals.

Project description:Background: Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABAA) receptor δ subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a δ-subunit-selective, extrasynaptic GABAA receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS. Methods: This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors. Results: A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (n = 8), 5 mg BID (n = 8), or 5 mg TID (n = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (n = 4), headache (n = 3), diarrhea (n = 2), and irritability (n = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement. Conclusions: Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03697161.

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Dataset Information

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.

Publications

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.

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