For decades, the development of antidepressants has focused on the development of agents targeting the reuptake of serotonin and norepinephrine. The discovery that ketamine has rapid antidepressant and anti-suicidal effects has led to the recognition that the glutamate system and N-methyl D-aspartate receptor (NMDAR) antagonists may play an important role in the treatment of depression and suicidality. While there has been considerable interest in the use of ketamine for depression; its use has been limited by the very short duration of its antidepressant effects and its potential for abuse.
Another medication with activity at the NMDA receptor is D-cycloserine (DCS), a broad-spectrum antibiotic used for the treatment of tuberculosis which also appears to have antidepressant effects. At doses below 50 mg per day, DCS primarily acts as an NMDA agonist; however, at doses greater than 500 mg per day, DCS acts as an NMDA receptor antagonist and has been shown to be effective for the treatment of depression. Unlike ketamine, DCS has shown no potential for neurotoxicity or abuse.
In a recent Phase 2 clinical trial, Andrew Nierenberg, MD, Director of the Dauten Family Center for Bipolar Treatment Innovation at Mass General Hospital, and colleagues examine whether NRX-101 (NRx Pharmaceuticals), a fixed-dose combination of DCS and the atypical antipsychotic lurasidone, can maintain improvement after treatment with intravenous ketamine more effectively than lurasidone alone in a group of patients with bipolar depression.
Does the Addition of D-Cycloserine Reduce Risk of Recurrent Symptoms?
In this multicenter study, 22 individuals with bipolar disorder who presented with depressive symptoms and suicidal ideation and/or behaviors received a single infusion of IV ketamine (n=17) or saline (n=5) during Stage 1 of the trial. Those who improved were randomized to a fixed-dose combination of DCS and lurasidone or lurasidone alone (Stage 2) with the goal of maintaining the improvement in depression achieved in Stage 1.
Depressive symptoms were assessed using the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thoughts and behaviors were measured using the Columbia Suicide Severity Rating Scale (C-SSRS). Global improvement was measured using the clinical global severity scale (CGI-S).
The combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvements in depression and reducing suicidal ideation. In addition, there was a non-statistically significant decrease in risk of depressive relapse (0% vs. 40%; p = 0.07). Treatment with NRX-101 did not cause any significant safety concerns and demonstrated improvements in patient-reported side effects. More specifically, there was an increase in akathisia observed in the lurasidone group, whereas a decrease in akathisia was seen in the NRX-101 cohort.
Next Steps
One of the challenges in using ketamine has been the short duration of its antidepressant effects. While many with severe depression and suicidality describe a significant improvement after a single dose of IV ketamine, their symptoms typically return within a few days.
While this was a small study, the results of this Phase 2 study including 22 patients with bipolar depression demonstrate that sequential treatment with ketamine followed by maintenance treatment with NRX-101, a combination of DCS and lurasidone, is more efficacious than maintenance treatment with lurasidone alone in maintaining reductions in depressive symptoms and suicidal ideation.
This combination of DCS and lurasidone might be a particularly attractive option for patients who require hospitalization due to acute suicidal ideation and/or behavior. In an inpatient setting, the patient could receive a single infusion of ketamine and, if sufficient improvement is observed, could be discharged on a regimen of lurasidone and D-cycloserine. On the basis of these positive findings, the FDA awarded a Breakthrough Therapy Designation and granted a Special Protocol Agreement for a Phase 3 registration trial of NRX-101 vs. lurasidone in patients with Severe Bipolar Depression and Acute Suicidal Ideation or Behavior (NCT03396068).
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Nierenberg A, Lavin P, Javitt DC, Shelton R, Sapko MT, Mathew S, Besthof RE, Javitt JC. 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. Int J Bipolar Disord. 2023 Aug 13;11(1):28.
Andrew Nierenberg, MD holds the Thomas P. Hackett, MD, Endowed Chair in Psychiatry at Massachusetts General and is the Director of the Dauten Family Center for Bipolar Treatment Innovation, Associate Director of the Depression Clinical and Research Program, and Co-Director of Center for Clinical Research Education, Division of Clinical Research at the Mass General Research Institute. Dr. Nierenberg is a professor of psychiatry at Harvard Medical School.
