Small Molecule · NRX-101

NRX-101 (D-cycloserine/lurasidone)

Phase 3NRx Pharmaceuticals, Inc. (NRXP)
  • FDA Fast Track (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; August 2017)
  • FDA Breakthrough Therapy (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; Announced 2018-11-13)

Oral fixed-dose combination of D-cycloserine (DCS), an NMDA receptor glycine-site modulator, and lurasidone, an approved atypical antipsychotic, developed by NRx Pharmaceuticals (through its subsidiary NeuroRx). Low-dose DCS acts as an NMDA partial agonist that can enhance synaptic plasticity, while high doses act as a functional NMDA antagonist; lurasidone offsets the psychotomimetic effects of DCS. NRX-101 holds FDA Breakthrough Therapy designation (2018) for severe bipolar depression with acute suicidal ideation and behavior. Two programs are active: a rolling NDA initiated for suicidal bipolar depression, and the DARPA-funded Phase 2/3 SPARC-TMS trial pairing NRX-101 with single-day robotic transcranial magnetic stimulation in treatment-resistant depression.

Also known as: NRX-101, NRX101, NRX 101, D-cycloserine/lurasidone, D-cycloserine, 68-41-7, lurasidone hydrochloride

Data current as of

Key facts

Modality
Small molecule
Mechanism
NMDA receptor Partial agonist
Highest phase
Phase 3
Lead indication
Bipolar depression
Developer
NRx Pharmaceuticals, Inc. (NRXP)
Designations
FDA Fast Track (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; August 2017), FDA Breakthrough Therapy (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; Announced 2018-11-13)
Trials
6 tracked · 1 recruiting · 26 sites
Next catalyst
December 2027 — Registry results (Treatment-resistant depression)

Mechanism of action#

Two-component NMDA-directed strategy. D-cycloserine binds the NMDA receptor and is dose-dependent: at low doses (50-100 mg) it functions as a partial agonist that can enhance synaptic plasticity, and at higher doses (>500 mg) as a functional antagonist. Lurasidone, an approved second-generation antipsychotic, offsets the psychotomimetic effects of D-cycloserine. NRx describes lurasidone as a 5-HT2A antagonist and states that it increases NMDA receptor expression through 5-HT7 antagonism. The bipolar depression program uses high-dose D-cycloserine, aiming to maintain ketamine-like NMDA antagonism. The TMS augmentation program uses a lower D-cycloserine dose, aiming to enhance the NMDA-dependent synaptic plasticity thought to drive TMS response.

TargetActionAffinity
NMDA receptorprimaryGRIN1Partial agonist—ⓘ
5-HT2AHTR2AAntagonist—ⓘ
5-HT7HTR7Antagonist—ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
NRX-101 oral capsule (high-dose D-cycloserine/lurasidone, twice daily)
Fixed-dose combination of D-cycloserine and lurasidone taken twice daily by mouth in the bipolar depression trials (NCT03395392, NCT03396068). The Glx biomarker pilot used D-cycloserine 950 mg + lurasidone 66 mg. A non-CNS urinary tract infection study (NCT06128213) used 487.5 mg DCS + 16.5 mg lurasidone HCl twice daily. Exact per-capsule strengths for the bipolar Phase 2b/3 trial are not stated in the sources opened.
OralTwice daily—
NRX-101 oral capsule (low-dose D-cycloserine/lurasidone, TMS augmentation)
D-cycloserine 175 mg + lurasidone 8.5 mg given with a single-day course of robotic neuronavigated theta-burst TMS in SPARC-TMS (NCT07227103). The McLean SPARC-LI pilot (NCT07785102) lists 175 mg D-cycloserine + 8.25 mg lurasidone as a single dose.
OralSingle dose—

Development timeline#

20182020202220242026TodayPhase 31 Jun 2026 — Partnership — NRx partners with Mass General-led Bipolar Action Network on an NRX-101 trial in treatment-resistant bipolar depression31 Jul 2025 — phase change — NRx submitted more than 80,000 pages of manufacturing, nonclinical and clinical material (the Module 3 file) to the FDA to begin a rolling NDA for NRX-101 in suicidal bipolar depression, and requested rolling review under its Breakthrough designation. The NDA is not complete, so phase stays phase_3 and not 'filed'. The 10-K gives the month only (July 2025); the date is the month-end anchor.30 Apr 2024 — readout (mixed) — Phase 2b/3 NRX-101 vs lurasidone in bipolar depression with subacute suicidal ideation (no ketamine lead-in): similar antidepressant effect (each about 50% MADRS reduction), a 33% advantage in sustained remission from suicidality that was not statistically significant, and about 70-75% less akathisia (P=0.076).13 Aug 2023 — readout (met) — STABIL-B (Phase 2) published: after ketamine stabilization, NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS difference -1.5, p=0.02; CGI-SS p=0.03) in 22 patients with severe bipolar depression and acute suicidality.1 Dec 2019 — phase change — The Phase 3 SBD-ASIB maintenance trial (NCT03396068), run under the FDA Special Protocol Agreement, started (actual start date per ClinicalTrials.gov). Registry status is now UNKNOWN (last updated 2024-01-19, estimated primary completion 2024-12-31, 72 estimated), and no results are posted.1 Aug 2017 — Fast Track — FDA grants Fast Track designation to NRX-101 for severe bipolar depression with acute suicidal ideation and behaviorPhase 213 Nov 2018 — Breakthrough Therapy — FDA grants Breakthrough Therapy designation to NRX-101 for suicidal bipolar depression15 Jan 2018 — phase change — STABIL-B (NCT02974010), a two-stage Phase 2 trial in severe bipolar depression with acute suicidal ideation, started (actual start date per ClinicalTrials.gov). Patients received a single ketamine or saline infusion, then NRX-101 or lurasidone. Primary completion 2018-08-31; 22 enrolled.Phase 2/331 Dec 2027 — upcoming — ClinicalTrials.gov estimated primary completion of the Phase 2/3 SPARC-TMS trial of NRX-101 plus robotic TMS in treatment-resistant depression: December 2027 (study completion estimated June 2028).30 Sept 2026 — Financing — NRx awarded $11 million DARPA prime contract for the SPARC-TMS trial of NRX-101 with robotic TMS12 Nov 2025 — phase change — SPARC-TMS (NCT07227103, NRX101-011) first posted on ClinicalTrials.gov as a Phase 2/3 study of NRX-101 vs placebo with robotic TMS for treatment-resistant depression. Registry estimated start 2026-12-01, so this date marks program entry by registration, not first patient dosed.12 Nov 2025 — Trial registered — SPARC-TMS Phase 2/3 trial of NRX-101 with robotic TMS registered on ClinicalTrials.gov
Phase change Readout Event UpcomingHover a marker for details.
Phase 2/3Nov 2025 – Dec 2027
  1. UpcomingClinicalTrials.gov estimated primary completion of the Phase 2/3 SPARC-TMS trial of NRX-101 plus robotic TMS in treatment-resistant depression: December 2027 (study completion estimated June 2028).Treatment-resistant depression
  2. FinancingNRx awarded $11 million DARPA prime contract for the SPARC-TMS trial of NRX-101 with robotic TMSTreatment-resistant depression↗
  3. SPARC-TMS (NCT07227103, NRX101-011) first posted on ClinicalTrials.gov as a Phase 2/3 study of NRX-101 vs placebo with robotic TMS for treatment-resistant depression. Registry estimated start 2026-12-01, so this date marks program entry by registration, not first patient dosed.Treatment-resistant depression
  4. Trial registeredSPARC-TMS Phase 2/3 trial of NRX-101 with robotic TMS registered on ClinicalTrials.govTreatment-resistant depression
Phase 3Aug 2017 – Jun 2026
  1. PartnershipNRx partners with Mass General-led Bipolar Action Network on an NRX-101 trial in treatment-resistant bipolar depressionBipolar depression↗
  2. NRx submitted more than 80,000 pages of manufacturing, nonclinical and clinical material (the Module 3 file) to the FDA to begin a rolling NDA for NRX-101 in suicidal bipolar depression, and requested rolling review under its Breakthrough designation. The NDA is not complete, so phase stays phase_3 and not 'filed'. The 10-K gives the month only (July 2025); the date is the month-end anchor.Bipolar depression↗
  3. mixedPhase 2b/3 NRX-101 vs lurasidone in bipolar depression with subacute suicidal ideation (no ketamine lead-in): similar antidepressant effect (each about 50% MADRS reduction), a 33% advantage in sustained remission from suicidality that was not statistically significant, and about 70-75% less akathisia (P=0.076).Bipolar depression↗
  4. metSTABIL-B (Phase 2) published: after ketamine stabilization, NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS difference -1.5, p=0.02; CGI-SS p=0.03) in 22 patients with severe bipolar depression and acute suicidality.Bipolar depression↗
  5. The Phase 3 SBD-ASIB maintenance trial (NCT03396068), run under the FDA Special Protocol Agreement, started (actual start date per ClinicalTrials.gov). Registry status is now UNKNOWN (last updated 2024-01-19, estimated primary completion 2024-12-31, 72 estimated), and no results are posted.Bipolar depression
  6. Fast TrackFDA grants Fast Track designation to NRX-101 for severe bipolar depression with acute suicidal ideation and behaviorBipolar depression↗
Phase 2Jan 2018 – Nov 2018
  1. Breakthrough TherapyFDA grants Breakthrough Therapy designation to NRX-101 for suicidal bipolar depressionBipolar depression↗
  2. STABIL-B (NCT02974010), a two-stage Phase 2 trial in severe bipolar depression with acute suicidal ideation, started (actual start date per ClinicalTrials.gov). Patients received a single ketamine or saline infusion, then NRX-101 or lurasidone. Primary completion 2018-08-31; 22 enrolled.Bipolar depression

NRX-101 (D-cycloserine/lurasidone) for Bipolar depression#

Phase 3ActiveBipolar depression indication →

NRX-101 (oral D-cycloserine/lurasidone) for bipolar depression with suicidal ideation, NRx Pharmaceuticals' original indication. The phase 2 STABIL-B trial (NCT02974010, n=22) gave patients a single ketamine infusion and then randomized them. NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS, p=0.02). On this basis the FDA granted Breakthrough Therapy designation in 2018 and a Special Protocol Agreement for a registrational trial. That Phase 3 maintenance trial (NCT03396068, SBD-ASIB) started in December 2019; its registry status is now unknown and no results are posted. A Phase 2b/3 comparison against lurasidone without prior ketamine (NCT03395392, n=74) reported in April 2024. The two drugs had similar antidepressant effects (each cut depression scores by about 50%). NRX-101 showed a 33% advantage in sustained remission from suicidality, which was not statistically significant, and a roughly 75% reduction in akathisia. In July 2025 NRx submitted the manufacturing (Module 3) portion of an NDA and requested rolling review under its Breakthrough designation. It aims for accelerated approval in bipolar depression with suicidal ideation despite approved medication, with akathisia as a key feature. In June 2026 it agreed to support an open-label trial in treatment-resistant bipolar depression run by the Mass General-led Bipolar Action Network.

Readouts

  • 2024-04-30ReportedTopline datamixedNCT03395392

    Phase 2b/3 NRX-101 vs lurasidone in bipolar depression with subacute suicidal ideation (no ketamine lead-in): similar antidepressant effect (each about 50% MADRS reduction), a 33% advantage in sustained remission from suicidality that was not statistically significant, and about 70-75% less akathisia (P=0.076). ↗

  • 2023-08-13ReportedFull resultsmetNCT02974010

    STABIL-B (Phase 2) published: after ketamine stabilization, NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS difference -1.5, p=0.02; CGI-SS p=0.03) in 22 patients with severe bipolar depression and acute suicidality. ↗

NRX-101 (D-cycloserine/lurasidone) for Treatment-resistant depression#

Phase 2/3ActiveTreatment-resistant depression indication →

NRX-101 (oral D-cycloserine/lurasidone at a low D-cycloserine dose) as an add-on to a single-day course of robotic, neuronavigated theta-burst transcranial magnetic stimulation (TMS) for treatment-resistant depression. The rationale is that TMS works through NMDA-dependent synaptic plasticity, which D-cycloserine (an NMDA partial agonist) may enhance. The Phase 2/3 SPARC-TMS trial (NCT07227103) is a randomized, double-blind, three-arm study planned for 240 TMS-naive adults with major depressive disorder. It compares NRX-101 with placebo, alongside active or sham TMS, with MADRS depression and CGI-SS suicidality as primary outcomes. Sites are McLean Hospital, Arizona State University and HOPE Therapeutics clinics, with military treatment facilities affiliated. DARPA selected NRx as prime contractor and on 2026-09-30 NRx announced an $11 million DARPA contract. NRx says success could support an NDA for NRX-101 with TMS. In June 2026 the FDA granted an intermediate-population Expanded Access Protocol for NRX-101 with accelerated TMS in treatment-resistant depression. A separate McLean-sponsored open-label pilot (SPARC-LI, NCT07785102) tests a single NRX-101 dose with single-day TMS.

Readouts

  • December 2027AnticipatedRegistry resultsNCT07227103

    ClinicalTrials.gov estimated primary completion of the Phase 2/3 SPARC-TMS trial of NRX-101 plus robotic TMS in treatment-resistant depression: December 2027 (study completion estimated June 2028).

Clinical trials#

NCT07227103NRX101-011Phase 2/3Recruitingn=240

A Randomized, Double-Blind Controlled Comparison of NRX-101 vs. Placebo for Adults Being Treated With Transcranial Magnetic Stimulation for Treatment Resistant Depression: The SPARC-TMS Trial

Started Dec 2026· Primary completion Dec 2027· 3 sites across 1 country

United States

NCT077851022026P001458Phase 0Activen=30

SPARC-LI: Single Day of Ultra-accelerated TMS With a Single Dose of NRX-101

Started Sept 2026· Primary completion Dec 2026

NCT03395392NRX101_003Phase 2/3Completedn=74

A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior

Started May 2022· Primary completion Feb 2024· 14 sites across 1 country

United States

NCT03396068NRX101_002Phase 3Unknownn=72

NRX-101 for Maintenance of Remission From Severe Bipolar Depression in Patients With Acute Suicidal Ideation and Behavior: The SBD-ASIB Study

Started Dec 2019· Primary completion Dec 2024· 4 sites across 1 country

United States

NCT03402152NRX101_004Phase 2/3Completedn=8

NRX101 Glx Biomarker Validation Study

Started Nov 2018· Primary completion Jan 2021· 1 site across 1 country

United States

Show all 6 trials

NCT02974010NRX 101-001Phase 2Completedn=22

Sequential Therapy for the Treatment of Severe Bipolar Depression (STABIL-B)

Started Jan 2018· Primary completion Aug 2018· 4 sites across 1 country

United States

Sources#

  1. Franzen AD, et al. Mechanism-Based Polypharmacy as a Repurposing Strategy: The Case of D-Cycloserine and Lurasidone. Clin Transl Sci. 2026;19(6):e70624 — Clinical and Translational Science / PubMed
  2. NCT02974010 (NRX 101-001, STABIL-B) — Sequential Therapy for the Treatment of Severe Bipolar Depression — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT03395392 (NRX101_003) — A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT03396068 (NRX101_002, SBD-ASIB) — NRX-101 for Maintenance of Remission From Severe Bipolar Depression in Patients With Acute Suicidal Ideation and Behavior — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03402152 (NRX101_004) — NRX101 Glx Biomarker Validation Study — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT07227103 (NRX101-011, SPARC-TMS) — A Randomized, Double-Blind Controlled Comparison of NRX-101 vs. Placebo for Adults Being Treated With Transcranial Magnetic Stimulation for Treatment Resistant Depression — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT07785102 (2026P001458, SPARC-LI) — Single Day of Ultra-accelerated TMS With a Single Dose of NRX-101 — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NeuroRx Receives FDA Breakthrough Therapy Designation for NRX-101, First Oral Drug Targeting Suicidal Bipolar Depression (2018-11-13) — NeuroRx, Inc. (via Business Wire / BioSpace)
  9. Nierenberg A, et al. 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;11(1):28 — International Journal of Bipolar Disorders / PubMed
  10. NRx Defense Systems Awarded $11 Million DARPA Prime Contract to Evaluate Robotic Magnetic Stimulation in conjunction with NRX-101 for Treatment Resistant Depression (press release 2026-09-30; Form 8-K Ex. 99.1 filed 2026-10-05) — NRx Pharmaceuticals, Inc. / SEC EDGAR
Show all 13 sources
  1. NRx Pharmaceuticals Announces Promising Findings in Phase 2b/3 Clinical Trial of NRX-101 vs. Lurasidone for Treatment of Suicidal Bipolar Depression (2024-04-30; Form 8-K Ex. 99.2) — NRx Pharmaceuticals, Inc. / SEC EDGAR
  2. NRx Pharmaceuticals Form 10-K for fiscal year 2025 (filed 2026-03-23) — NRx Pharmaceuticals, Inc. / SEC EDGAR
  3. NRx Pharmaceuticals Form 10-Q for the quarter ended June 30, 2026 (filed 2026-08-14) — NRx Pharmaceuticals, Inc. / SEC EDGAR