NRX101 Glx Biomarker Validation Study

Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the followingcriteria apply:

1. 18 to 65 years of age, inclusive, at screening.
2. Able to understand and provide written and dated informed consent prior to screening.Deemed likely to comply with study protocol and communicate AEs and other clinicallyimportant information, and agree to be hospitalized to complete screening and initiateexperimental treatment.
3. Resides in a stable living situation, in the opinion of the investigator
4. Has an identified reliable informant, in the opinion of the investigator
5. Diagnosed with bipolar disorder (BD) according to the criteria defined in the DSM-5.The diagnosis of BD will be made by a psychiatrist and supported by the MINI 7.0.2.
6. Suicidal ideation or behavior as evidenced by an answer of "Yes" to item 2 or item 3on the C-SSRS.
7. A score of greater than or equal to 20 on the MADRS.
8. In good general health, as ascertained by medical history, physical examination (including measurement of seated vital signs), clinical laboratory evaluations, andelectrocardiogram
9. If female, a status of non-childbearing potential or use of an acceptable form ofbirth control per the following specific criteria:
10. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant,i.e., permanently sterilized [status post hysterectomy, bilateral tuballigation], or post-menopausal with last menses at least one year prior toscreening); or
11. Childbearing potential, and meets the following criteria: i. Using any form of hormonal birth control, on hormone replacement therapy startedprior to 12 months of amenorrhea, using an intrauterine device (IUD), having amonogamous relationship with a partner who has had a vasectomy, or sexually abstinent. ii. Negative urinary pregnancy test at screening, confirmed by a second negativeurinary pregnancy test at randomization prior to receiving study treatment. iii. Willing and able to continuously use one of the following methods of birthcontrol during the course of the study, defined as those which result in a low failurerate (i.e., less than 1% per year) when used consistently and correctly: implants,injectable or patch hormonal contraception, oral contraceptives, IUD, double-barriercontraception, sexual abstinence. The form of birth control will be documented atscreening and pre-ketamine baseline.
12. Body mass index between 18-35kg/m2.
13. Concurrent psychotherapy will be allowed if the type and frequency of the therapy (e.g., weekly or monthly) has been stable for at least three months prior to screeningand is expected to remain stable for the duration of the study.
14. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin,benzodiazepines, or trazodone) will be allowed if the therapy has been stable for atleast four weeks prior to screening and if it is expected to remain stable during thecourse of the subject's participation in the study. Subjects can also continuetreatment with benzodiazepines used for anxiety if therapy has been stable for atleast four weeks prior to screening and if it is expected to remain stable during thecourse of the subject's participation in the study.

Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteriaapply:

1. Female of childbearing potential who is not willing to use one of the specified formsof birth control during the study.
2. Female who is pregnant or breastfeeding.
3. Female with a positive pregnancy test at screening or before oral dosing ofinvestigational product.
4. Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuanaor tobacco use disorder) within the 12 months prior to screening. Substance abusecannot be the precipitant of entry to treatment.
5. Subjects with a lifetime history of PCP/ketamine drug use, or failed use of ketaminefor depression.
6. History of schizophrenia or schizoaffective disorder, or any history of psychoticsymptoms when not in an acute bipolar mood episode.
7. History of anorexia nervosa, bulimia nervosa, or eating disorder NOS (OSFED) withinfive years of screening.
8. Has dementia, delirium, amnestic, or any other cognitive disorder.
9. Any major psychiatric disorder, including a personality disorder, which is clinicallypredominant to BD at screening, or has been the primary focus of treatment predominantto BD at any time within six months prior to screening.
10. Current major psychiatric disorder, diagnosed at screening with the MINI 7.0.2, thatis the primary focus of treatment, with BD as the secondary focus of treatment, withinthe past six months.
11. A clinically significant abnormality on the screening physical examination that mightaffect safety or study participation, or that might confound interpretation of studyresults according to the study clinician.
12. Current episode of:
13. Untreated hypertension, (Stage 1 or greater) as defined by a systolic bloodpressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at screening on two ofthree measurements at least 15 minutes apart. If untreated due to missingmedication dose/s this is not exclusionary.
14. Hypertension, Stage 2, as defined by a systolic blood pressure ≥155 mmHg ordiastolic blood pressure ≥99 mmHg within 1.5 hours prior to ketamine infusion ontwo of three measurements at least 15 minutes apart at the pre-ketamineassessment (on Day 0 at Visit 1).
15. Recent myocardial infarction (within one year).
16. Syncopal event within the past year.
17. Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2.
18. Angina pectoris.
19. Heart rate <50 or >105 beats per minute at screening, pre-ketamine infusion (Day

0. or at randomization (Day 1).

8. QTcF ≥450 msec at screening for men, ≥ 470 msec for women, pre-ketamine infusion (Day 0), or at randomization (Day 1), on two of three measurements at least 15minutes apart.
9. History of hypertension, or on antihypertensives for the purpose of lowering bloodpressure, with either an increase in antihypertensive dose or increase in the numberof antihypertensive drugs used to treat hypertension over the last two months.
10. Chronic lung disease, excluding asthma.
11. Lifetime history of surgical procedures involving the brain or meninges, encephalitis,meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's orParkinson's Disease), epilepsy, mental retardation, or any otherdisease/procedure/accident/intervention that, according to the screening clinician, isdeemed associated with significant injury to or malfunction of the CNS; or history ofsignificant head trauma within the past two years.
12. Presents with any of the following lab abnormalities: a. Subjects with diabetes mellitus fulfilling any of the following criteria: i.Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.0 % atscreening. ii. Admitted to hospital for treatment of diabetes mellitus or diabetesmellitus-related illness in the past 12 weeks. iii. Not under physician care for diabetes mellitus. iv. Has not been on the same doseof oral hypoglycemic drug(s) and/or diet for the four weeks prior to screening. Forthiazolidinediones (glitazones) this period should not be less than eight weeks. b. Any other clinically significant abnormal laboratory result (as determined by theinvestigator and medical monitor) at the time of the screening.
13. Any current or past history of any physical condition which, in the investigator'sopinion, might put the subject at risk or interfere with study results interpretation.
14. Subjects on exclusionary concomitant psychotropic medications (see Appendix 1) asdefined in the study manual.
15. At randomization, subjects prescribed more than one agent in each category;
16. Approved antidepressants (e.g., SSRIs, SNRIs, TeCAs, fluoxetine), but not 5-HT-2aantagonists (lurasidone, aripiprazole, olanzapine, quetiapine)
17. Mood stabilizers (e.g., lithium, carbamazepine, valproic acid)
18. Subjects with exclusionary laboratory values (see Table 2).
19. Known allergies to lurasidone or Latuda, cycloserine or Seromycin, or the excipientsmannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or HPMC (hydroxypropylmethylcellulose).
20. Participation in any clinical trial with an investigational drug or device within thepast month or concurrent to study participation.
21. Study site personnel and/or persons employed by NeuroRx, Inc. or Target Health or bythe investigator or study site (i.e., permanent, temporary contract worker, ordesignee responsible for the conduct of the study), or an immediate family member (i.e., spouse or parent, child, or sibling [biological or legally adopted]) of suchpersons.