Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes.

DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When a one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week.

This trial will compare response and remission at six weeks following neuronavigated robotic-enabled Transcranial Magnetic Stimulation + NRX-101 (D-cycloserine/lurasidone) vs. TMS+placebo.

Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes.

rTMS and TBS are believed to depend on synaptic plasticity in targeted circuits. Yet, there are several lines of evidence to suggest that synaptic plasticity is not intact in MDD, such as impaired learning and memory and lower expression of trophic factors.Using TMS as a tool to probe synaptic plasticity, individuals with MDD have reduced long-term potentiation-like facilitation in the motor cortex and prefrontal cortex. Importantly, this is observed with the intermittent TBS (iTBS) protocol used in MDD treatment. As such, iTBS treatment effects may be constrained by impaired synaptic plasticity in MDD.

One potential strategy to improve outcomes is to adjunctively target the N-methyl-D-aspartate (NMDA) receptor during stimulation, an ionotropic glutamate receptor and key regulator of synaptic plasticity.Synaptic plasticity with continuous and intermittent TBS is NMDA-receptor dependent, as antagonists abolish the effects of both protocols.We have shown that targeting the NMDA receptor with low doses of the partial agonist, D-cycloserine (DCS), normalizes long-term motor cortex plasticity in individuals with MDD. Moreover, it results in greater persistence of iTBS-induced changes compared with placebo.However, a demonstration that these physiological effects have an impact on treatment outcomes is needed

DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When a one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week.

This trial will compare response and remission at six weeks following neuronavigated robotic-enabled Transcranial Magnetic Stimulation + NRX-101 (D-cycloserine/lurasidone) vs. TMS+placebo.

18 to 65 years of age, inclusive, at Screening. 2. Participants must be initiating a new course of TMS treatment and must be TMS-naïve. 3. Able to understand and provide written and dated informed consent prior to Screening. 4. Deemed likely to comply with the study protocol, including communication of adverse events (AEs) and other clinically important information, including adherence to the text messaging component of the trial. 5. Previously diagnosed with major depressive disorder (MDD) according to the criteria defined in the DSM-5. 6. Has treatment-resistant MDD defined as failure to achieve an adequate response after at least two adequate antidepressant trials of different agents, each given at a therapeutic dose and for sufficient duration. 7. A total score ≥ 25 on the 10 items of the MADRS. 8. Has an identified reliable informant/care partner that is willing to provide information and/or supportive care as necessary. 9. If heterosexual female, a status of non-childbearing potential or use of an acceptable form of birth control per the following criteria, and agrees to continue use of the same method of birth control for the duration of study participation:

1. Non-childbearing potential: physiologically incapable of becoming pregnant (i.e., permanently sterilized [status posthysterectomy, bilateral tubal ligation], or post-menopausal with last menses at least one year prior to Screening); or
2. Childbearing potential, and meets the following criteria:

i. Must agree to use at least one highly effective method of birth control (methods which result in a failure rate of less than 1% per year when used consistently and correctly) during study participation. Examples of acceptable highly effective methods include established use of oral, injected, implanted, or intrauterine hormonal contraception; placement of an intrauterine device or intrauterine system; or a vasectomized partner with documented azoospermia; or true sexual abstinence that is the participant's usual and preferred lifestyle. ii. Negative urinary pregnancy test at Screening, confirmed by a second negative urinary pregnancy test at Day 1, prior to receiving study treatment. 10. Body mass index (BMI) between 18-40 kg/m2; BMI up to 45 kg/m2 is allowed with Medical Monitor review and approval. 11. If receiving concurrent psychotherapy, the type and frequency of the therapy (e.g., weekly or monthly) has been stable for at least 3 months prior to Screening and will remain stable for the duration of study participation. 12. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, maximum 2 mg daily, or trazodone) will be allowed if the therapy has been stable for at least 4-weeks prior to screening and will remain stable during the course of the patient's participation in the study. 13. Concurrent treatment with benzodiazepines is allowed up to a maximum dose 2 mg/daily used for anxiety if therapy has been stable relative to dose and schedule for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the patient's participation in the study. Exclusion criteria: A patient is ineligible for inclusion in this study Heterosexual female of childbearing potential who is not willing to use one of the specified forms of birth control during the study. 2. Female who is pregnant (positive pregnancy test at Screening) or breastfeeding. 3. Active suicidality (without the intention to act) as evidenced by a score of >3 on the Columbia Suicide Severity Rating Scale. 4. Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to Screening. (Note: Substance use disorder cannot be the precipitant for study entry). 5. Current DSM-5 diagnosis of alcohol use disorder 6. A lifetime history of phencyclidine (PCP)/ketamine drug abuse 7. History of schizophrenia or schizoaffective disorder 8. History of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified (NOS), or other specified feeding and eating disorders (OSFED) within 3 years of Screening. 9. Has dementia, delirium, amnestic, or any other cognitive disorder. 10. Renal impairment defined as estimated glomerular filtration rate (eGFR) < 60 mL/min, calculated using the 2021 CKD-EPI creatinine equation (racefree). 11. Clinically significant hepatic impairment. Clinically significant hepatic impairment is defined as a history of chronic liver disease (e.g., cirrhosis, chronic hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis) or evidence at Screening of acute liver disease or impaired liver function (e.g., ALT or AST >3 × ULN, total bilirubin >2 × ULN) or in the opinion of the Investigator. 12. A clinically significant abnormality on the Screening physical examination that may affect safety or study participation, or that may confound interpretation of study results according to the study clinician. 13. Risk factors for neurocardiogenic syncope including history of syncope/ presyncope related to noxious stimuli, anxiety, micturation, or posture. 14. Co-morbidities as ascertained by medical history, physical examination (including measurement of vital signs), clinical laboratory evaluations, and electrocardiogram (ECG) which might interfere with compliance or the ability to assess efficacy or safety. 15. Diagnosis of moderate to severe heart disease or current episode of:

1. Myocardial infarction within 1 year of Screening.
2. Diagnosis of angina pectoris.
3. Prolonged QTc interval, as measured by Fridericia's correction formula (QTcF) ≥450 msec at Screening for males or ≥ 470 msec for females on 2 of 3 measurements at least 15 minutes apart prior to randomization on Day 1. 16. Diagnosis of chronic lung disease, excluding asthma. 17. Lifetime history of any of the following: neurologic conditions with structural cerebral damage, traumatic brain injury, multiple sclerosis, surgical procedures involving the brain or meninges, meningoencephalitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's Disease, Parkinson's Disease), mental retardation, stroke (ischemic or hemorrhagic), intracranial abscess, or any other disease/procedure/accident/intervention that, according to the clinician, is deemed associated with significant injury to, or malfunction of, the CNS. 18. History of epilepsy, personal history of seizure, family history of epilepsy or seizure in a first degree relative. 19. Diagnosis of parenchymal or leptomeningeal cancer.

Diabetes mellitus fulfilling any of the following criteria:

1. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.0 percent at Screening.
2. Admitted to the hospital for treatment of diabetes mellitus or diabetes mellitus-related illness in the past 12 weeks.
3. Not under physician care for diabetes mellitus.
4. Not on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks prior to Screening. 180645 180645 Protocol NRX101-011_ MIND1 V3.0 FINAL Pg. 8 NRX101-011 Protocol v3.0 9 Confidential
5. Not on the same dose of oral thiazolidinediones (glitazones) for the 8 weeks prior to Screening. 21. Any current or past history of any physical condition which, in the opinion of the investigator, may put the patient at risk or interfere with study results interpretation. 22. On exclusionary concomitant psychotropic and non-psychotropic medications (see Section 9.5) 23. Prescribed more than one agent in each of the following categories at randomization:

a. Approved SSRIs. b. Approved serotonin and norepinephrine reuptake inhibitors (SNRIs). c. Approved tetracyclic antidepressants (TeCAs). 24. Currently prescribed oxcarbazepine or carbamazepine. 25. Exclusionary laboratory values or any other clinically significant abnormal laboratory result at Screening. Within normal limits (WNL) will be determined based on lab values of the local lab used. 26. Known allergies to lurasidone or Latuda®, cycloserine or Seromycin®, or the following excipients: mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or hydroxypropylmethylcellulose (HPMC). 27. Participation in any clinical trial with an investigational drug or device within the past 3 months or planned concurrent study participation. 28. Study site personnel and/or persons employed by NRx Pharma, Inc., the Contract Research Organization (CRO), the investigator, or study site (i.e., permanent, temporary contract worker, or designee responsible for the conduct of the study), or an immediate family member (i.e., spouse, parent, child, or sibling [biological or legally adopted]) of such persons. Positive urine toxicity screening for use of any cocaine, opiates, nonprescribed amphetamines, or non-prescribed barbiturates. (Note: cannabinoids or marijuana use is not exclusionary, unless patient meets the DSM-5 criteria for cannabis withdrawal). 30. Patients with pacemakers and/or any implants including metal in the head except the mouth (cochlear implant, implanted brain stimulators, aneurysm clips) 31. Individuals with an intracranial lesion or increased intracranial pressure

upon study inception

Protocol and ICF shared with all SAP and CSR upon signed confidentiality agreement

Matched drug and placebo capsules