Non-superiority of zuranolone (SAGE-217) at the longer-term

Doesschate, Freek ten; Waarde, Jeroen A. van; Wingen, Guido van

doi:10.1016/j.jad.2021.05.015

Cited by 11 publications

(6 citation statements)

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“…The overall efficacy and safety of zuranolone (up to 50-mg once-daily dose) have been demonstrated in phase 2 and 3 clinical trials conducted in patients with MDD. [28][29][30][31][32][33] The 14-day treatment regimen of zuranolone demonstrated a rapid onset of activity with clinically meaningful improvements in depressive symptoms, which may offer the potential to treat MDD episodically as needed. [29][30][31][32][33] In Japan, a phase 1 study showed no major safety and tolerability issues (Sonoyama et al, article under submission).…”

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confidence: 99%

“…We speculate that zuranolone supplements the weakened GABA‐enhancing effect of allopregnanolone, and is thought to exert a rapid‐acting antidepressant effect through a mechanism of action different from that of existing antidepressants. The overall efficacy and safety of zuranolone (up to 50‐mg once‐daily dose) have been demonstrated in phase 2 and 3 clinical trials conducted in patients with MDD 28–33 . The 14‐day treatment regimen of zuranolone demonstrated a rapid onset of activity with clinically meaningful improvements in depressive symptoms, which may offer the potential to treat MDD episodically as needed 29–33 …”

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Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double‐blind, randomized, placebo‐controlled, phase 2 clinical trial

Kato

Nakagome

Baba

et al. 2023

Psychiatry Clin Neurosci

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AimTo evaluate the efficacy and safety of an oral, once‐daily, 14‐day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD).MethodsThis multicenter, randomized, double‐blind, placebo‐controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment‐period), followed by two 6‐week follow‐up periods. The primary endpoint was change from baseline in the 17‐item Hamilton Depression Rating Scale (HAMD‐17) total score on Day 15.ResultsOverall, 250 patients (enrolled: 07/07/2020–05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD‐17 total score on Day 15 was −6.22 (0.62), −8.14 (0.62), and − 8.31 (0.63) in the placebo, zuranolone 20‐mg, and zuranolone 30‐mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (−1.92; [−3.65, −0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (−2.09; [−3.83, −0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug‐placebo separation was observed during follow‐up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone.ConclusionOral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD‐17 total score change from baseline over 14 days in Japanese patients with MDD.

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Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double‐blind, randomized, placebo‐controlled, phase 2 clinical trial

Kato

Nakagome

Baba

et al. 2023

Psychiatry Clin Neurosci

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“…In general, zuranolone exhibited antidepressant effect on day 3 and sustained until day 45. However, the real long-term efficacy of zuranolone requires to be discussed because the results were influenced by the data from a forest plot of two included studies (performed by Deligiannidis et al on PPD) ( Ten Doesschate et al, 2021 ; Arnaud and Bonthapally, 2022 ; Ten Doesschate et al, 2022 ). For MDD, no statistical difference was observed on day 45; two phase III studies (MOUNTAIN and WATERFALL) also showed no statistically significant difference on day 42 ( Ten Doesschate et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of zuranolone in patients with depression: a meta-analysis of randomized controlled trials

Qiu,

Tao,

Duan

et al. 2024

Front. Pharmacol.

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Background: As a novel antidepressant drug, zuranolone has been initially applied in treating depression. This study investigated the efficacy and safety of its administration in patients with depression.Methods: The Embase, PubMed, and Cochrane library databases were searched for available studies up to 1 Nov 2023. The primary outcome was the change on day 15 depression severity scores compared to baseline. Secondary outcomes included remission and response rates on day 15. Safety outcomes included incidence of treatment-emergent adverse events (TEAEs) and individual AEs. Trial sequential analysis (TSA) was used to evaluate the ideal samplesize.Results: Six studies with 1884 patients were included. Zuranolone offered significantly greater changes in day 15 depression severity scores (mean difference = 2.43, 95% confidence interval [CI]: 1.36 to 3.49, p < 0.00001) compared to placebo; this was also observed at other time points. Differences in response (relative risk [RR] = 1.33, 95% CI: 1.15 to 1.54, p < 0.0001) and remission (RR = 1.46, 95% CI: 1.15 to 1.85, p = 0.002) rates were also statistically significant. For safety outcomes, zuranolone group showed more incidence of TEAE than the placebo group (RR: 1.15, 95% CI: 1.06 to 1.25, p = 0.0005, I2 = 0%). As for individual AEs, significant differences were observed in dizziness (RR = 2.17, 95% CI: 1.22 to 3.86, p = 0.008) and somnolence (RR = 2.43, 95% CI: 1.35 to 4.37, p = 0.003. No significant difference was observed in other AEs. The result of TSA indicated that the cumulative curve crossed the conventional (Z = 1.96) boundary but not reach TSA boundary (RIS = 1910).Conclusion: Our findings suggest that zuranolone has a rapid short-term antidepressant effect during administration. Although more TEAEs were observed in zuranolone, most of them were slight and temporary. However, studies with larger sample sizes and longer follow-up are needed.Systematic Review Registration:https://inplasy.com/inplasy-2023-5-0104/, identifier INPLASY202350104.

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“…F. Š. would like to acknowledge the financial support from the Czech Science Foundation (project no. 19…”

Section: Acknowledgementsmentioning

confidence: 99%

“…13,[15][16][17] Interestingly, a recently concluded Phase III study has shown that significant improvement of MDD symptoms has been achieved for an oral dose of 30 mg but not for 20 mg. 18 Existing data demonstrate efficacy mostly at approximately the two-week mark, with the desired effect slowly tapering off. 19,20 As evidenced by the above-mentioned studies, neurosteroidbased drugs can exhibit non-trivial dose-response relationships and complex temporal effects. It is therefore important to investigate this class of substances more thoroughly both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

Chvíla,

Kubová,

Mareš

et al. 2024

RSC Pharm.

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Non-superiority of zuranolone (SAGE-217) at the longer-term

Cited by 11 publications

References 4 publications

Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double‐blind, randomized, placebo‐controlled, phase 2 clinical trial

Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double‐blind, randomized, placebo‐controlled, phase 2 clinical trial

Efficacy and tolerability of zuranolone in patients with depression: a meta-analysis of randomized controlled trials

A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

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