Medically Reviewed by Mark Hrymoc, M.D., Chief Medical Officer, double-board certified in General & Addiction Psychiatry
Suicidal ideation in major depressive disorder and bipolar depression remains a public health emergency, with U.S. deaths by suicide reaching historically high levels in recent years. Against this backdrop, NRx Pharmaceuticals has advanced two investigational agents that target this gap: NRX-100, a preservative-free intravenous ketamine, and NRX-101, an oral fixed-dose combination of D-cycloserine and lurasidone. Understanding how FDA pathways such as Fast Track and Accelerated Approval work, and where these programs may apply, helps clarify what patients, families, and clinicians might expect as development moves forward.
Where NRX-100 and NRX-101 Fit Clinically
NRX-100 is being studied for rapid relief of acute suicidal ideation in depression, including bipolar depression. Ketamine’s rapid antidepressant effect is well documented, but its clinical use has been limited by temporary benefit and the need for monitored infusion. A proprietary, preservative-free formulation positioned for acute crises is being developed. NRX-101 combines D-cycloserine, a glutamatergic modulator at the NMDA receptor, with lurasidone, an atypical antipsychotic approved for bipolar depression and schizophrenia. The goal is to sustain antidepressant and anti-suicidal benefit after initial stabilization, while potentially reducing akathisia and other tolerability issues seen with antipsychotics alone. Recent controlled studies and company reports suggest NRX-101 may reduce suicidality more rapidly and cause less akathisia than lurasidone monotherapy, with comparable antidepressant effects, although broader confirmatory evidence is still needed for full approval.
What the FDA Has Formally Recognized So Far
The FDA has granted multiple development advantages across the program. NRX-101 has previously received Breakthrough Therapy designation and a Special Protocol Agreement for pivotal study design, as well as Fast Track status, reflecting early evidence that the therapy may offer substantial improvement over existing options for suicidal bipolar depression. NRX-100 was granted Fast Track designation in August 2025 for suicidal ideation in depression, including bipolar depression, which enables rolling review and more frequent FDA interaction. These designations do not mean the drugs are approved; they signal that the FDA acknowledges the seriousness of the condition and the potential for benefit, and they can expedite review once adequate data are submitted.
Evidence Snapshot From Clinical Trials
Early work with hospital-presenting patients in severe bipolar depression and acute suicidality used NRX-100 for rapid stabilization, followed by randomized maintenance with NRX-101 versus lurasidone. In that setting, the combination appeared to better maintain improvement in depressive symptoms and reduce suicidal ideation versus lurasidone alone, with favorable tolerability signals. A subsequent phase 2b/3 outpatient study compared NRX-101 directly to lurasidone without prior ketamine, reporting comparable antidepressant effects but faster reduction in suicidality and less akathisia on the combination. These findings inform ongoing regulatory strategy, but larger confirmatory evidence and FDA review will determine approvability.
How Accelerated Approval Could Apply
The Accelerated Approval pathway allows the FDA to approve therapies for serious conditions based on a surrogate endpoint reasonably likely to predict clinical benefit, with a postmarketing requirement to confirm outcomes. Company statements indicate plans to submit NRX-101 for Accelerated Approval targeting suicidal bipolar depression with akathisia and active suicidal ideation despite standard care, supported by phase 2b/3 data and earlier SPA-guided trials. NRX-100 is likewise being advanced toward NDA submission, now with the added support of Fast Track. Until NDAs are accepted and reviewed, these remain investigational agents. Patients and clinicians should rely on currently approved standards while monitoring developments.
Suicide Awareness and Why Timely Relief Matters
In 2022, the United States recorded 49,476 deaths by suicide, the nation’s 11th leading cause of death, with provisional data showing similarly high numbers in 2023. Rapid reduction in suicidal ideation is clinically meaningful because the period following an emergency visit for self-harm or suicidal thoughts is a time of sharply elevated risk. Innovations aimed at shortening time to relief, improving tolerability, and sustaining remission could translate into fewer crises and better continuity of care. If you or someone you know is in immediate danger, call or text 988 in the U.S. to reach the Suicide and Crisis Lifeline.
Physician Suicide and the Health System Context
Suicide awareness must include the workforce that delivers care. Recent analyses show complex, sex-specific patterns in physician suicide rates compared with the general population; some studies note elevated risk among female physicians, while others report nuanced or narrowing gaps. Addressing clinician burnout, access to confidential care, and stigma is essential, both ethically and because clinician well-being influences system capacity to deliver timely crisis care.
What Patients and Families Can Do Now
Work with licensed clinicians to build a safety plan for suicidality. Ask about evidence-based treatments that can reduce suicidal thoughts, including optimized pharmacotherapy and psychotherapies such as CBT or DBT. For individuals with bipolar depression, ensure careful diagnostic assessment because some antidepressants may worsen course without appropriate mood stabilization. As investigational options like NRX-100 and NRX-101 advance, consider clinical trial participation when appropriate and discuss the balance of potential benefits and risks within shared decision-making.
Bottom Line
Fast Track and Breakthrough Therapy designations for the NRX program, together with SPA-guided trials and plans for Accelerated Approval submissions, underscore urgent unmet needs in suicidal depression. NRX-100 aims to deliver standardized, rapid stabilization for acute crises, while NRX-101 targets sustained reduction in suicidality and improved tolerability compared with lurasidone alone. These developments warrant cautious optimism. Until the FDA completes review and, if appropriate, grants approval, these agents remain investigational, and established emergency pathways and evidence-based treatments should remain the foundation of care.
References
- Psychiatrist.com. How NRx Could Upend the Fight Against Depression and Suicide. Aug 29, 2024.
- NRx Pharmaceuticals. FDA Designations. Accessed 2025.
- PR Newswire. NRx Announces Data Lock of Phase 2b/3 Trial of NRX-101. Apr 8, 2024.
- ClinicalTrials.gov. NRX-101 for Maintenance of Remission From Severe Bipolar Depression With Acute Suicidal Ideation and Behavior. NCT03396068.
- NRx Pharma IR. Company anticipates NDA for Accelerated Approval of NRX-101. 2025 filings.
- Psychiatric Times. FDA Fast Track Designation for NRX-100. Aug 11, 2025.
- BioSpace. FDA Grants Fast Track Designation for NRX-100. Aug 12, 2025.
- CDC NCHS Data Brief. Suicide Mortality in the United States, 2002–2022. 2024.
- CDC FastStats. Suicide and Self-Inflicted Injury, 2023 data. 2025.
- JAMA Psychiatry. National Incidence of Physician Suicide and Associated Factors. 2025.
