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
A. Nierenberg, P. Lavin, D. Javitt, Richard Stewart Shelton, M. T. Sapko, S. Mathew, R. Besthof, J. Javitt
International Journal of Bipolar Disorders August 13, 2022 DOI: 10.1186/s40345-023-00308-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Multi-center, double-blind, two-stage, parallel randomized trial Peer reviewed |
|---|---|
| Sample size | 22 |
| Population | Adult patients with bipolar disorder with severe depression and acute suicidal ideation or behavior requiring hospitalization |
| Interventions | Ketamine D-cycloserine Lurasidone |
| Measures | Montgomery Åsberg Depression Rating Scale (MADRS), Columbia Suicide Severity Rating Scale (C-SSRS), clinical global severity scale (CGI-S), CGI-SS |
| Topics | Depression Esketamine Ketamine |
| Registration | NCT02974010 |
| Key findings | After a single ketamine infusion, a fixed-dose combination of D-cycloserine and lurasidone maintained improvement in depression and reduced suicidal ideation more effectively than lurasidone alone, with no significant safety events. The authors propose this sequential regimen as a promising therapeutic approach and note it received FDA Breakthrough Therapy Designation and a Special Protocol Agreement. |
Abstract
Background: 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.
Methods: 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). Clinicaltrials.gov NCT02974010; Registered: November 22, 2016.
Results: 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.
Conclusions: 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.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.