What is the mechanism of action of this treatment?

NMDA antagonists, such as ketamine, work by blocking the N-methyl-D-aspartate (NMDA) receptor, which is involved in glutamate neurotransmission. This can lead to rapid antidepressant effects and reduction in suicidal ideation, making them valuable for treatment-resistant depression and severe bipolar depression. Serotonin-dopamine antagonists, like lurasidone, block serotonin and dopamine receptors, helping to stabilize mood and reduce symptoms of mania and depression. These mechanisms are crucial as they offer alternative pathways for patients who do not respond to traditional treatments, providing hope for more effective management of their conditions.

What side effects are associated with this type of intervention?

Common treatments for depression and bipolar disorder that are similar to NRX-101 include NMDA antagonists like ketamine and serotonin-dopamine antagonists like lurasidone. NMDA antagonists can cause side effects such as dizziness, impaired gait, nasal discomfort, and pain on urination. Serotonin-dopamine antagonists, such as lurasidone, may lead to side effects including weight gain, metabolic changes, and extrapyramidal symptoms like tremors or rigidity. Both classes of drugs require careful monitoring due to their potential impact on the central nervous system.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of depression and bipolar disorder that are similar to NRX-101, which combines an NMDA antagonist and a serotonin-dopamine antagonist. Ketamine, an NMDA antagonist, has been approved for treatment-resistant depression in the form of esketamine (Spravato). Lurasidone, a serotonin-dopamine antagonist, is approved for the treatment of bipolar depression. These approvals highlight the therapeutic potential of targeting both NMDA receptors and serotonin-dopamine pathways in managing mood disorders.

What other types of research exist?

Promising novel alternatives to NRX-101 for depression and bipolar disorder include: 1) MK-0657, a selective NR2B antagonist, which showed potential antidepressant efficacy in a pilot trial for treatment-resistant major depressive disorder. 2) BTRX-246040, a NOP antagonist, which has been characterized as a potent and selective antagonist with potential antidepressant properties. These alternatives are based on recent clinical evaluations and pharmacological characterizations.

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NMDA Antagonist

NRX-101 for Bipolar Depression (SBD-ASIB Trial)

Phase 3

Waitlist Available

Research Sponsored by NeuroRx, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Diagnosed with bipolar disorder (BD) according to the criteria defined in the DSM-5

18 to 65 years of age, able to understand and provide written and dated informed consent prior to screening

Must not have

Clinically significant abnormality on the screening physical examination

Any major psychiatric disorder clinically predominant to BD at screening

Timeline

Screening 3 weeks

Treatment Varies

Follow Up six weeks

Awards & highlights

No Placebo-Only Group

All Individual Drugs Already Approved

Pivotal Trial

Approved for 5 Other Conditions

Summary

This trial tests a two-step treatment for adults with severe bipolar depression and suicidal thoughts. It starts with a quick-acting ketamine dose followed by an oral medication to maintain improvement. The goal is to see if this approach is better than using lurasidone alone. Ketamine has been shown to rapidly reduce depressive and suicidal symptoms in both unipolar and bipolar depression.

Who is the study for?

Adults aged 18-65 with severe bipolar depression and suicidal thoughts, responding to initial treatment under NCT03396601. Participants must be in good health, have a stable living situation, reliable informant, and if female, use effective birth control or be non-childbearing. Excludes those with other major psychiatric disorders as primary focus or certain physical conditions.

What is being tested?

The trial tests NRX-101 for maintaining remission from severe bipolar depression after initial stabilization with IV ketamine (NRX-100). NRX-101 is compared to Lurasidone alone over six weeks of oral dosing. The study aims to see if NRX-101 better prevents relapse and reduces suicidal thoughts.

What are the potential side effects?

Possible side effects include typical antidepressant risks like nausea, headaches, dizziness but also may involve unique reactions due to the novel combination of D-cycloserine and lurasidone in NRX-101.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with bipolar disorder.

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I am between 18 and 65 years old and can understand and sign a consent form.

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I am not able to have children or I am using reliable birth control.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My screening exam showed a significant health issue.

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I have a major psychiatric condition more prominent than bipolar disorder.

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I am not willing to use birth control as required.

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I am currently pregnant or breastfeeding.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 6 weeks

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~6 weeks

This trial's timeline: 3 weeks for screening, Varies for treatment, and 6 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

MADRS-10

Secondary study objectives

Time to Relapse (stage 2)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Approved for 5 Other Conditions

This treatment demonstrated efficacy for 5 other conditions.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: NRX-101Experimental Treatment1 Intervention

Subjects will be treated with oral NRX-101 (fixed dose combination of D-Cycloserine/lurasidone) that will be titrated to a combined dose of 950mg/66mg per day.

Group II: Lurasidone comparatorActive Control1 Intervention

Subjects will be treated with oral lurasidone in a matched placebo capsule that will be titrated to a dose of 66 mg per day

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

NRX-101

2022

Completed Phase 3

~90

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

NMDA antagonists, such as ketamine, work by blocking the N-methyl-D-aspartate (NMDA) receptor, which is involved in glutamate neurotransmission. This can lead to rapid antidepressant effects and reduction in suicidal ideation, making them valuable for treatment-resistant depression and severe bipolar depression. Serotonin-dopamine antagonists, like lurasidone, block serotonin and dopamine receptors, helping to stabilize mood and reduce symptoms of mania and depression. These mechanisms are crucial as they offer alternative pathways for patients who do not respond to traditional treatments, providing hope for more effective management of their conditions.

Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis.