NRX-101 · program

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

Phase 2/3ActiveNRx Pharmaceuticals, Inc. (NRXP)

Indications for NRX-101: Bipolar depression · Phase 3 Treatment-resistant depression · Phase 2/3

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.

Data current as of

Development timeline

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).
  2. FinancingNRx awarded $11 million DARPA prime contract for the SPARC-TMS trial of NRX-101 with robotic TMS↗
  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.
  4. Trial registeredSPARC-TMS Phase 2/3 trial of NRX-101 with robotic TMS registered on ClinicalTrials.gov

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 in Treatment-resistant depression

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

Formulations

FormulationRouteRegimenPharmacokinetics
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—

Mechanism of action (compound-wide)

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—ⓘ

← Full NRX-101 compound page (identity, identifiers, all indications)

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. 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)
  3. 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)
  4. 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)
  5. 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