A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD)

Inclusion Criteria: 1. Male or female, 18 to 65 years of age, inclusive, at screening. 2. Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information. 3. Diagnosed with MDD, single or recurrent, and currently experiencing a major depressive episode (MDE) of at least eight weeks in duration, prior to screening, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of MDD will be made by a site psychiatrist and supported by the SCID-5. The diagnosis will be confirmed by remote, independent raters from the MGH CTNI (Massachusetts General Hospital Clinical Trials Network and Institute) with a SAFER interview. 4. Has a history of treatment resistant depression (TRD) during the current MDE, as assessed by the investigator and remote centralized rater using the MGH ATRQ. TRD is defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms), as perceived by the participant, to at least 2 "treatment courses" during the current episode of a therapeutic dose of an antidepressant therapy (ADT) of at least 8 weeks duration (including the current ADT). The adequacy of dose and duration of the antidepressant therapy will be determined as per the MGH ATRQ criteria. The TRD status will be confirmed by remote, independent raters from the MGH CTNI who will administer the MGH ATRQ, via teleconference, between the screening visit and the baseline visit. Participants must currently be on a stable (for at least 4 weeks) and adequate (according to the MGH ATRQ) dose of ongoing antidepressant therapy (any antidepressant therapy, with the exception of MAOIs), of which total duration must be at least 8 weeks. 5. Meet the threshold on the total MADRS score of \>20 at both the screen visit and the baseline visit (Day -7/-28 and Day 0), and as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit. 6. In good general health, as ascertained by medical history, physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, and ECG. 7. If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria: * Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or * Childbearing potential, and meets the following criteria: * Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent. * Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment. * Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and baseline. 8. Body mass index between 18-35 kg/m2. 9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented, et al.) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject's participation in the study. 10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Patients can also continue treatment with benzodiazepines used for anxiety if therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Exclusion Criteria: 1. Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study. 2. Female that is pregnant or breastfeeding. 3. Female with a positive pregnancy test at screening or baseline. 4. History during the current MDE of failure to achieve satisfactory response (e.g., less than 50% improvement of depression symptoms) to \>7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration, according to the MGH ATRQ, as confirmed by the remote, independent MGH CTNI rater. 5. Total MADRS score of \<20 at the screen visit or the baseline visit, or as assessed by the remote, independent MGH CTNI rater and reported to the site. 6. Current diagnosis of a substance use disorder (abuse or dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, at screening or within 6 months prior to screening. 7. Current Axis I disorder, diagnosed at screening with the use of the Structured Clinical Interview for DSM-5 AXIS I Disorders (SCID-5), that is the principal focus of treatment and MDD the secondary focus of treatment for the past 6 months or more. 8. History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes. 9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within 5 years of screening. 10. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within 6 months prior to screening. 11. In the judgment of the investigator, the subject is considered at significant risk for suicidal behavior during the course of his/her participation in the study. 12. Has failed to respond to ECT during the current depressive episode. 13. Has received VNS at any time prior to screening. 14. Has dementia, delirium, amnestic, or any other cognitive disorder. 15. Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results according to the study clinician. 16. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation. 17. Current episode of: * Hypertension, Stage 1 as defined by a systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mHg at the Baseline Visit (Visit 1) within 1.5 hours prior to randomization on two of three measurements (standing and supine) at least 15 minutes apart. * Recent myocardial infarction (within one year) or a history of myocardial infarction. * Syncopal event within the past year. * Congestive heart failure (CHF) New York Heart Association Criteria \>Stage 2 * Angina pectoris. * Heart rate \<45 or \>110 beats per minute at screening or randomization (Baseline Visit). * QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit). 18. Chronic lung disease excluding asthma. 19. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention which, according to the screening clinician, is deemed associated with significant injury to or malfunction of the CNS, or history of significant head trauma within the past 2 years. 20. Presents with any of the following lab abnormalities: * Thyroid stimulating hormone (TSH) outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant. * Patients with diabetes mellitus fulfilling any of the following criteria: * Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>8.5% at screening. * Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus-related illness in the past 12 weeks. * Not under physician care for diabetes mellitus. * Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than 8 weeks. * Any other clinically significant abnormal laboratory result (determined as such by the investigator and MGH CTNI medical monitor) at the time of the screening. 21. History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than 2 months prior to screening. (Subjects on a stable dosage of thyroid replacement medication for at least 2 months or more prior to screening are eligible for enrollment.) 22. History of hyperthyroidism which was treated (medically or surgically) less than 6 months prior to screening. 23. History of positive screening urine test for drugs of abuse at screening: cannabinoids (if the patient has a legitimate medical prescription for cannabis, patient must agree to abstain during the entirety of the study and to have a negative test at baseline), cocaine, amphetamines, barbiturates, opiates (unless use is in accordance with guidance provided in table of allowed and excluded medications). 24. Patients with exclusionary laboratory values (see Table 1), or requiring treatment with exclusionary concomitant medications (see Appendix 1). 25. Patients on exclusionary concomitant psychotropic medications, the half-life of which would not allow sufficient time for patients to have been free of the medication post-taper for five half-lives within the maximum screening period (28 days). 26. Patients with a history of narrow angle glaucoma. 27. Liver or renal Function tests which meet the exclusion criteria in Table 1, or a history of hepatic or renal dysfunction.