This is a double-blind, randomized, placebo-controlled, multicenter study comprised of 3 phases:screening (up to 2 weeks [Day -15 to Day -2]), In-Clinic Treatment (Day -1 to Day 2; including double-blind treatment [Day 1]), and post-treatment follow-up (7 and 14 days after infusion on Days 8 and 15, respectively). A total of 93 adult subjects with TRD will be randomly allocated in equal cohorts of 31 subjects/arm to the 3 arms of the study in a blinded manner.

Inclusion Criteria:

• Capable of giving and give signed informed consent
• Weigh >= 50 kg and have a body mass index >= 18 and <= 35
• Diagnosis of recurrent major depressive disorder (MDD) without psychotic features per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), confirmed by Mini-International Neuropsychiatric Interview
• Hamilton Depression Rating Scale total score > 20
• Inadequate response to at least 2 antidepressants in the current episode of depression that were given for >= 6 weeks
• Stable oral antidepressant treatment without dose change for at least 30 days

Exclusion Criteria:

• History of, or current signs and symptoms of diseases or conditions that would make participation not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments
• History of moderate or severe head trauma or other neurological disorders, neurodegenerative disorder or systemic medical diseases that are in the opinion of the Investigator likely to interfere with the conduct of the study or confound the study assessments
• Has a primary DSM-V diagnosis of current (active) MDD with psychotic features, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa.
• Has a current of prior DSM-V diagnosis of a primary psychotic disorder, bipolar or related disorders, intellectual or autism spectrum disorder, or borderline personality disorder
• Has any significant disease or disorder that in the opinion of the investigator, may either put the subject at risk because of participation in the study, influence the results of the study, or affect the subject's ability to participate in the study
• Has uncontrolled hypertension, despite medication, at Screening systolic blood pressure > 160 mm Hg or diastolic blood pressure > 90 mm Hg or any past history of hypertensive crisis.
• Has an abnormal ECG of clinical relevance at screening or baseline
• Has known history of, or positive serology for human immunodeficiency virus, hepatitis B surface antigen, hepatitis C infection
• Has a history of malignancy within the 5 years prior to screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy that in the opinion of the investigator, with concurrence with the Sponsor's Medical Monitor, is considered to have minimal risk of recurrence)
• Has homicidal ideation/intent per the Investigator's clinical judgment, or has suicidal ideation with some intent to act within 1 month prior to the start of screening per the Investigator's clinical judgement or based on the C-SSRS, or a history of suicidal behavior within the past year prior to the start of the screening/prospective observational phase
• Has had major surgery within the 4 weeks before screening, or will not have fully recovered from surgery or planned surgery during the time the subject is expected to participate in the study
• Has moderately impaired hepatic function at screening, defined as serum alanine aminotransferase or aspartate aminotransferase > 2 × upper limit of normal or total bilirubin > 2 × upper limit of normal
• Has received any disallowed therapies as follows:
• Receipt of a known potent inhibitor of hepatic cytochrome P450 (CYP) 2B6, or CYP3A, activity within 1 week or within a period 5 times the drug's half-life, whichever is longer, before the first administration of study drug on Day 1
• Treatment with a disallowed antipsychotic within the past 30 days prior to screening, except subjects who are on stable doses of quetiapine, aripiprazole, brexpiprazole, or olanzapine prescribed as adjunct treatment for depression (without psychosis) may be included in the study
• Any changes in psychotropic medication type or dose within the past 30 days prior to screening
• Treatment with monoamine oxidase inhibitors currently or within the past 30 days of screening
• Doses of oral contraception should not contain more than 30 micrograms of ethinyl estradiol per day
• Has initiated psychotherapy or acupuncture acupuncture within the past 90 days of screening. Patients planning to initiate individual or group therapy during the study are also not eligible
• Has received electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, or other brain stimulation treatment within the past 4 weeks or currently used as either an acute or maintenance treatment of depression
• Has received any IP within 30 days or 5 half-lives
• Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within the previous 6 months prior to the screening visit
• Has a history of previous nonresponse to ketamine, R-ketamine or S-ketamine, or has received 8 or more doses of ketamine, R-ketamine or S-ketamine in their lifetime
• Has a previous history of intolerance to ketamine, R-ketamine, or S-ketamine
• History of abuse of ketamine, R-ketamine, S-ketamine, or phencyclidine
• Subjects should not consume grapefruit, grapefruit juice, or Seville orange related products for 72 hours before IP administration and throughout the study
• Has the presence of clinically relevant long-term COVID-19 symptoms. Has current signs or symptoms of COVID-19
• COVID-19 vaccination is allowed as long as the doses are administered ≥ 30 days before study drug administration; vaccination is not allowed during the course of the study