The British journal of psychiatry : the journal of mental science · 2026
A Phase 2 randomised, double-blind, placebo-controlled trial of emestedastat in patients with major depressive disorder and cognitive impairment.
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Taylor Jack D, Rolan Paul E, Jaros Mark J, Harrison John E, Ratcliffe Stuart H, Berk Michael, Hilt Dana C
Аннотация
BACKGROUND: 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.
AIMS: 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.
METHOD: Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks' blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery-Åsberg 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's d effect size. No adjustments were made for multiple comparisons.
RESULTS: 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 z-score was -1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 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's d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild-moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group.
CONCLUSIONS: 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.
AIMS: 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.
METHOD: Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks' blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery-Åsberg 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's d effect size. No adjustments were made for multiple comparisons.
RESULTS: 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 z-score was -1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 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's d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild-moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group.
CONCLUSIONS: 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.