Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression

* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Ability of participant to understand and willingness to sign a written informed consent document. To verify this, participants must score \>= 80% on the consent quiz. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. 18 to 70 years of age. 4. All participants must have undergone a screening assessment under protocol 01-M-0254. 5. Participants must fulfill DSM-IV or DSM-5 criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Participants must be experiencing a current major depressive episode lasting at least two weeks. 6. Participants must have an initial score of \>= 20 on the MADRS and a YMRS score of \<12 within one week of study entry and upon entry into Phase II. 7. Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen. 8. Participants must have a current or past history of lack of response to at least one adequate antidepressant trial (may be from the same chemical class), with at least one in the current major depressive episode, operationally defined using the modified Antidepressant Treatment History Form (ATHF); non-response to an adequate trial of ECT or TMS would count as an adequate antidepressant trial. 9. For individuals of reproductive potential: use of highly effective contraception starting at the time of enrollment and agreement to use such a method during study participation and for an additional four weeks after the end of Study Phase II. 10. For males of reproductive potential: use of condoms or other methods from the time of enrollment to ensure effective contraception with partner, and for an additional 90 days after the end of Phase II. 11. Agreement to adhere to Lifestyle Considerations throughout study duration. 12. Medically healthy, or with stable, treated, chronic medical conditions (provided any medications are not excluded) EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: 1. Current use of disallowed concomitant medications or transcranial magnetic stimulation (TMS) two weeks prior to the start of Phase II. 2. Treatment with a reversible monoamine oxidase inhibitor (MAOI) four weeks prior to the start of Phase II. 3. Treatment with fluoxetine, aripiprazole, or brexpiprazole five weeks prior to the start of Phase II. 4. Treatment with clozapine or electroconvulsive therapy (ECT) four weeks prior to the start of Phase II. 5. Ongoing treatment with moderate or strong CYP3A4/5 inhibitors or inducers 6. Lifetime history of deep brain stimulation. 7. Previous antidepressant non-response to ketamine or esketamine (full course). 8. No structured psychotherapy will be permitted during the total duration of the study. Participants unable or unwilling to stop psychotherapy will be unable to participate in the study. 9. Pregnancy or lactation. 10. Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5. 11. Participants with a history of DSM-IV substance or alcohol abuse or dependence, or DSM-5 substance use disorder (except for caffeine, nicotine, or cannabis), or moderate to severe alcohol use disorder, within the preceding three months. In addition, participants who are currently using drugs (except for caffeine, nicotine, or cannabis) must not have used illicit substances or known drugs of abuse in the two weeks prior to screen and must have a negative drug urine test (except for prescribed benzodiazepines or stimulants) prior to starting Phase II. Cannabis use is exclusionary if the use is daily, or if participants are unable to abstain during the study, or if function of daily life is impaired by use as determined by a clinician. Due to the interactions between cannabis and SSRIs, frequent cannabis use during previous antidepressant treatment will result in that treatment being considered a failed trial for eligibility purposes. 12. Participants with a DSM-IV or DSM-5 Axis II diagnosis of borderline or antisocial personality disorder. 13. Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes (for the imaging component of the study). 14. No serious, unstable medical illnesses including but not limited to the following body systems and organs or those that in the judgment of the Principal Investigator pose a risk to the participant's ability to safely participate in the study: Hepatic diseases (e.g. active viral hepatitis infection or cirrhosis of the liver, any liver disease with Child-Pugh score \>=5), cardiovascular disease (including ischemic heart disease, coronary artery disease, congestive heart failure, poorly controlled hypertension due to risk of further blood pressure elevation and increase in demand on cardiac function from study drug), renal/urologic (e.g chronic kidney disease or acute kidney injury, history of bladder dysfunction due to theoretical risk of ketamine-induced cystitis, moderate to severe renal impairment of any etiology), endocrinologic (including uncontrolled diabetes due to association with progressive abnormality of the microvasculature and nervous system), or neurologic disease (e.g. elevated intraocular pressure or history of or presence of diseases that are associated with elevated intracranial pressure). 15. Participants with unstable clinical hyperthyroidism or hypothyroidism. 16. Participants with one or more seizures without a clear and resolved etiology. 17. Clinically significant abnormal laboratory tests specifically defined by: * Alkaline phosphatase (Alk Phos) \> 150 U/L * Alanine aminotransferase (ALT) \> 55 U/L * Aspartate aminotransferase (AST) \> 34 U/L * Total bilirubin (TB) \> 1.2 mg/dL * Direct bilirubin (DB) \> 0.5 mg/dL * 25-hydroxyvitamin D \< 20 ng/mL * Folate \< 2ng/mL * Vitamin B12 \< 200 pg/mL 18. Moderate to severe renal impairment with body surface area corrected eGFR \<60mL/min. 19. Participants who, in the Principal Investigator's judgment, pose a current serious suicidal or homicidal risk. 20. Positive HIV test. 21. Contraindications to MRS (metal in body, claustrophobia, etc. for imaging) 22. Participants with COVID-19 or suspected COVID-19 23. Inability to read and understand English. Non- English speakers will not be eligible as most of the required monitoring and rating instruments are not validated in languages other than English.