Nierenberg Andrew, Lavin Philip, Javitt Daniel C, Shelton Richard, Sapko Michael T, Mathew Sanjay, Besthof Robert E, Javitt Jonathan C
Massachusetts General Hospital, Boston, MA, USA.
Lavin Consulting LLC, Framingham, MA, USA.
Int J Bipolar Disord. 2023 Aug 13;11(1):28. doi: 10.1186/s40345-023-00308-5.
We 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.
This 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).
gov NCT02974010; Registered: November 22, 2016.
Thirty-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.
Sequential 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.
我们检验了这样一个假设，即对于伴有严重抑郁及急性自杀观念或行为的双相情感障碍（BD）患者，在静脉注射氯胺酮后病情初步改善后，口服D -环丝氨酸（DCS）与鲁拉西酮（NRX - 101）的固定剂量组合比单独使用鲁拉西酮能更有效地维持病情改善。
这是一项多中心、双盲、两阶段、平行随机试验。伴有抑郁及自杀观念或行为的成年BD患者接受氯胺酮或生理盐水输注（第1阶段）；病情改善的患者被随机分为DCS与鲁拉西酮固定剂量组合组和单独使用鲁拉西酮组（第2阶段），以维持第1阶段取得的病情改善。采用蒙哥马利 - 阿斯伯格抑郁评定量表（MADRS）测量抑郁程度，采用哥伦比亚自杀严重程度评定量表（C - SSRS）测量自杀观念和行为；采用临床总体严重程度量表（CGI - S）测量总体改善情况。
美国国立医学图书馆临床试验注册中心编号NCT02974010；注册时间：2016年11月22日。
37例患者接受筛查，22例患者入组、随机分组并接受治疗。第1阶段接受治疗的所有22例患者（17例接受氯胺酮治疗，5例接受生理盐水治疗）均进入第2阶段，11例完成研究。DCS与鲁拉西酮的固定剂量组合在维持抑郁改善（MADRS LMS Δ - 7.7；p = 0.03）以及降低自杀观念方面显著优于单独使用鲁拉西酮，自杀观念通过C - SSRS（Δ - 1.5；p = 0.02）和CGI - SS（Δ - 2.9；p = 0.03）测量，且抑郁复发有非统计学意义的降低（0%对40%；p = 0.07）。这种序贯治疗方案未引起任何显著的安全事件，且患者报告的副作用有所改善。
对于因急性自杀观念和行为而需要住院治疗的双相抑郁患者，单次输注氯胺酮后序贯使用NRX - 101维持治疗是一种有前景的治疗方法，可减轻抑郁和自杀观念。基于这些发现，该疗法被授予突破性疗法认定，美国食品药品监督管理局（FDA）批准了一项特殊方案协议用于注册试验。
