['depressive disorder, major', 'depressive disorder, treatment-resistant']
['rel-1017', 'placebo']

        Inclusion Criteria:

          1. Males between 18 and 65 years of age, inclusive; and females between 18 and 65 years
             of age, inclusive, who are >1 year postmenopausal.

          2. Diagnosed with recurrent MDD as defined by the Diagnostic and Statistical Manual,
             Fifth Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric
             Interview, Version 7.0.2 (MINI).

          3. Diagnosed with a current MDE lasting 8 weeks to 36 months as defined by the DSM-5 and
             confirmed by the MINI.

          4. Treated with an adequate dosage of a SSRI, SNRI, or bupropion during the current MDE
             for at least 8 weeks prior to Screening with the same, adequate dosage for the last 4
             weeks. Minimum adequate doses are defined in the (ATRQ). The maximum dose allowed for
             paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and for sertraline is 200 mg QD.

          5. Have experienced an inadequate response to 1 to 3 courses of treatment with an
             antidepressant medication in the current episode, as defined as <50% improvement with
             an antidepressant medication at doses listed on the SAFER Interview Criteria: State
             versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps
             (pervasive, persistent, and pathological).

          6. Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at Screening and Check-in (Day -1).

          7. BMI between 18.0 and 35.0 kg/m2, inclusive, and a minimum weight of 50.0 kg.

          8. Per the Investigator's judgment, able to meet all study requirements, including the
             confined/inpatient portion of the study, adherence with both approved ADT and study
             drug regimen, and completion of all assessments and all scheduled visits.

          9. Male patients of reproductive potential must be using and willing to continue using
             medically acceptable contraception, from Screening and for at least 2 months after the
             last study drug administration.

         10. Must be able to read, speak, and understand English and must provide written informed
             consent prior to the initiation of any protocol-specific procedures.

        Exclusion Criteria:

          1. History or presence of clinically significant abnormality as assessed by physical
             examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in
             the opinion of the Investigator would jeopardize the safety of the patient or the
             validity of the study results, including torsades de pointes, any bradyarrhythmias, or
             uncompensated heart failure.

          2. Chronic use of prescribed opioids (i.e., >120 days in a 6-month period) up to 6 months
             prior to Screening or any recreational use of opioids.

          3. Evidence of clinically significant hepatic or renal impairment, including ALT or AST
             >1.5 x upper limit of normal (ULN), bilirubin >1 x ULN, or endocrine laboratory values
             (including clinically significant thyroid parameters, i.e., thyroid stimulating
             hormone [TSH], triiodothyronine [T3], and thyroxine [T4]).

          4. History or family history of sudden unexplained death or long QT syndrome (measure of
             the time between the start of the Q wave and the end of the T wave in the heart's
             electrical cycle).

          5. Any 12-lead ECG with repeated demonstration of QTc ≥450 msec or a QRS interval >120
             msec at Screening.

          6. History of clinically diagnosed hypotension requiring treatment.

          7. History or presence of any condition in which an opioid is contraindicated (e.g.,
             significant respiratory depression, acute or severe bronchial asthma or hypercarbia,
             bronchitis, or has/is suspected of having paralytic ileus).

          8. No more than 3 prescribed doses of an opioid within the 6 months prior to Screening
             and no use at all within the last month.

          9. Use of an antipsychotic, anticonvulsant, or mood stabilizer, regardless of indication,
             within the 3 months prior to Screening.

         10. History of allergy or hypersensitivity to methadone or related drugs (e.g., opioids).

         11. Positive test for hepatitis B or HIV. Patients with a positive hepatitis C test may be
             considered for inclusion with approval from the Medical Monitor.

         12. Any current and primary psychiatric disorder, as defined as a condition that is the
             primary focus of distress and/or treatment, other than MDD.

         13. Any lifetime history of bipolar I or II disorder, any psychotic disorder,
             post-traumatic stress disorder, borderline personality disorder, antisocial
             personality disorder, obsessive compulsive disorder, eating disorder, intellectual
             disability, or pervasive developmental disorder.

         14. History in the past 12 months of a primary diagnosis of anxiety disorder or panic
             disorder not related to the current MDE.

         15. Current diagnosis of alcohol or substance use disorder, as defined by DSM-5, at
             Screening or within the 12 months prior to Screening. Patients with the following
             diagnoses within the past 12 months, however, may be included at the Investigator's
             discretion: mild alcohol use disorder, mild cannabis use disorder, and any severity
             tobacco use disorder.

         16. A confirmed positive result on the urine drug/alcohol screen at Screening or Check-in.
             If the urine drug/alcohol screen is positive at Screening, retesting or rescreening
             may be scheduled with prior approval from the Medical Monitor.

         17. Patients who, in the Investigator's judgment, are at significant risk for suicide. A
             patient with a Columbia-Suicide Severity Rating Scale (C-SSRS) ideation score of 4 or
             5 within the last 6 months or any suicide attempt within the past year must be
             excluded, as should a patient with an ideation score of 4 or 5 or any suicide attempt
             at the Check-in or Baseline Visit.

         18. Patients with a 20% improvement between Screening and Check-in (Day -1) on the
             HAM-D-17.

         19. Patients who did not safely discontinue medications prohibited.

         20. Patients receiving new onset psychotherapy (individual, group, marriage, or family
             therapy) within 2 months prior to Screening or plans to start at any time during
             participation in the study.

         21. Patients who have received electroconvulsive therapy (ECT), repetitive transcranial
             magnetic stimulation (rTMS), or vagus nerve stimulation (VNS) or who have participated
             in a ketamine study within the last 6 months.

         22. Patients with any clinically significant neurological, hepatic, renal, metabolic,
             hematological, immunological, cardiovascular, pulmonary, chronic pain, or
             gastrointestinal disorder. Medical conditions that are minor or well-controlled may be
             permitted if they will not increase the safety risk to the patient or compromise
             interpretation of the safety or efficacy endpoints.

         23. Patients taking fluvoxamine or St. John's Wort.

         24. Patients who have participated in a clinical study with an investigational medication
             in the past 6 months, or who have participated in more than 4 clinical studies with
             investigational medications in the past 2 years.
      