NRX100 vs. Placebo for Rapid Stabilization of Acute Suicidal Ideation and Behavior in Bipolar Depression

Background and Rationale: NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. Specifically, NRX-100 (ketamine HCl, 0.5 mg/kg IV over 40 minutes) has been shown to induce acute reductions in suicidality and depression in patients with bipolar depression, relative to control. Numerous reports have documented a 50% reduction in the MADRS depression scale and a 75% reduction in suicidality following a single infusion of ketamine in patients with suicidal ideation and depression. While the repeat use of ketamine is not supported and may be contraindicated by the literature, D-cycloserine (DCS), when combined with SSRI antidepressants in patients with treatment resistant depression, and when combined with atypical antipsychotics, in particular lurasidone (NRX-101), has shown separation from control and ability to maintain remission from suicidality and depression over 6 weeks with oral use.

Primary Objective:

• To test the hypothesis that a single infusion of NRX-100 is superior to placebo infusion in the rapid stabilization of patients with severe Bipolar Depression and Acute Suicidal Ideation and Behavior (ASIB).

Secondary Objectives:

• Key secondary: To test the hypothesis that there is a more favorable reduction in the mean change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) between NRX-100 and saline groups on day 1 and day 2.

Methodology: A multi-center, randomized, double-blind, trial involving a single IV infusion to achieve response by 24 hours. The randomization will be 3:1 favoring NRX-100 (ketamine) infusion (n=105) vs. Saline infusion (n=35). Subjects who respond successfully to treatment will be offered enrollment in a six week followup study of NRX-101 (an oral fixed dose combination of d-cycloserine and lurasidone) vs. standard of care in order to ascertain maintenance of the ketamine effect.