NRX-101 (D-cycloserine plus lurasidone) vs. lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior: a randomized prospective phase 2 trial

International Journal of Bipolar Disorders

Research

Sanjay Mathew¹  Daniel C. Javitt²  Philip Lavin³  Andrew Nierenberg⁴  Michael T. Sapko⁵  Robert E. Besthof⁵  Jonathan C. Javitt⁶  Richard Shelton⁷ 

[1] Baylor College of Medicine, Houston, TX, USA;Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA;NRx Pharmaceuticals, Inc, 1201 N Market St Suite 111, 19801, Wilmington, DE, USA;Lavin Consulting LLC, Framingham, MA, USA;Massachusetts General Hospital, Boston, MA, USA;NRx Pharmaceuticals, Inc, 1201 N Market St Suite 111, 19801, Wilmington, DE, USA;NRx Pharmaceuticals, Inc, 1201 N Market St Suite 111, 19801, Wilmington, DE, USA;Johns Hopkins University, Baltimore, MD, USA;University of Alabama at Birmingham, Birmingham, AL, USA;

关键词: Bipolar disorder;    Depression;    Suicidal ideation;    Ketamine;    Lurasidone Hydrochloride;    Cycloserine;   

DOI  :  10.1186/s40345-023-00308-5

 received in 2023-05-04, accepted in 2023-07-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundWe tested the hypothesis that, after initial improvement with intravenous ketamine in patients with bipolar disorder (BD) with severe depression and acute suicidal thinking or behavior, a fixed-dose combination of oral D-cycloserine (DCS) and lurasidone (NRX-101) can maintain improvement more effectively than lurasidone alone.MethodsThis was a multi-center, double-blind, twostage, parallel randomized trial. Adult BD patients with depression and suicidal ideation or behavior were infused with ketamine or saline (Stage 1); those who improved were randomized to a fixed-dose combination of DCS and lurasidone vs. lurasidone alone (Stage 2) to maintain the improvement achieved in Stage 1. Depression was measured by the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thinking and behavior was measured by the Columbia Suicide Severity Rating Scale (C-SSRS); global improvement was measured by the clinical global severity scale (CGI-S). Clinicaltrials.gov NCT02974010; Registered: November 22, 2016.ResultsThirty-seven patients were screened and 22 were enrolled, randomized, and treated. All 22 patients treated in Stage 1 (17 with ketamine and 5 with saline) were enrolled into Stage 2, and 11 completed the study. The fixed-dose combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvement in depression (MADRS LMS Δ-7.7; p = 0.03) and reducing suicidal ideation, as measured by C-SSRS (Δ-1.5; p = 0.02) and by CGI-SS (Δ-2.9; p = 0.03), and with a non-statistically significant decrease in depressive relapse (0% vs. 40%; p = 0.07). This sequential treatment regimen did not cause any significant safety events and demonstrated improvements in patient-reported side effects.ConclusionsSequential treatment of a single infusion of ketamine followed by NRX-101 maintenance is a promising therapeutic approach for reducing depression and suicidal ideation in patients with bipolar depression who require hospitalization due to acute suicidal ideation and behavior. On the basis of these findings, Breakthrough Therapy Designation was awarded, and a Special Protocol Agreement was granted by the FDA for a registrational trial.

【 授权许可】

CC BY   
© Springer-Verlag GmbH Germany, part of Springer Nature 2023

【 图 表 】

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