Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Brief Summary: The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.


Options:
A: Inclusion Criteria:

* Male or female, 18-70 years old.
* Able to read, understand, and provide written, dated informed consent prior to screening.
* Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening.
* Has a history of TRD during the current MDE.
* Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits (Day -7/-28 and Day 0), as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit.
* In good general health
* For female participants, status of non-childbearing potential or use of an acceptable form of birth control
* Body mass index between 18-35 kg/m2
* Concurrent psychotherapy will be allowed if the type and frequency of the therapy has been stable for at least three months prior to screening and is expected to remain stable during participation in the study
* Concurrent hypnotic therapy 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.

Exclusion Criteria:

* Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study
* Female that is pregnant or breastfeeding
* Female with a positive pregnancy test at screening or baseline
* History during the current MDE of failure to achieve a satisfactory response to \>7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode
* Total MADRS score of \<20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site
* Current diagnosis of a Substance Use Disorder (Abuse or Dependence) with the exception of nicotine dependence, at screening or within 6 months prior to screening
* Current Axis I disorder that is the principal focus of treatment and MDD the secondary focus of treatment for the past 6 months or more
* History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes
* History of eating disorders within five years of screening
* Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant at any time within 6 months prior to screening
* Subject is considered at significant risk for suicidal behavior during the course of their participation in the study
* Has failed to respond to electroconvulsive therapy (ECT) during the current depressive episode
* Has received vagus nerve stimulation (VNS) at any time prior to screening
* Has dementia, delirium, amnestic, or any other cognitive disorder
* Has a clinically significant abnormality on the screening physical examination
* Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation
* Current episode of:

  1. Hypertension, Stage 1 as defined by a systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements (standing and supine) at least 15 minutes apart.
  2. Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg 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.
  3. Recent myocardial infarction (within one year) or a history of myocardial infarction.
  4. Syncopal event within the past year.
  5. Congestive heart failure (CHF) New York Heart Association Criteria \>Stage 2
  6. Angina pectoris.
  7. Heart rate \<50 or \>105 beats per minute at screening or randomization (Baseline Visit).
  8. QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit).
* Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, who have either had an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last 2 months.
* Chronic lung disease excluding asthma.
* Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder, epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years
* Presents with any of the following lab abnormalities:

  1. Thyroid stimulating hormone 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.
  2. Patients with diabetes mellitus fulfilling any of the following criteria:

  i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>8.5% at screening ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks iii. Not under physician care for diabetes mellitus iv. 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.

  c. Any other clinically significant abnormal laboratory result (as determined after evaluation by study investigator and MGH CTNI medical monitor) at the time of the screening exam.
* 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.)
* History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening
* Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation
* History of positive screening urine test for drugs of abuse at screening
* Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications
* 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).
* Patient who have participated in studies of ketamine or AZD6765 or other NMDA receptor antagonists for depression and received active treatment.
* Patients with narrow angle glaucoma
* Patients with a lifetime history of PCP/Ketamine drug use
* Liver Function Tests higher than 2.5 times upper limit of normal
B: Inclusion Criteria:

* At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18) to 64 years of age, inclusive
* At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to \[\>=\] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
* At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (\>=) 34
* At the start of the screening/prospective observational phase, participant must have had non-response (greater than or equal to \[\<=25\] percent \[%\] improvement) to ≥1 but less than or equal to (\<=) 5 (if current episode is \>2 years, upper limit is applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by medical history and pharmacy/prescription records, for the current episode of depression. In addition, the participant is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose
* The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score \>=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment

Exclusion Criteria:

* Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release \[XR\]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
* Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
* Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
* Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
* Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
C: Inclusion Criteria:

1. Provision of written informed consent before initiation of any study-related procedures.
2. Eligible subjects who have consented to standard ECT treatment for their mood disorder and are willing to accept randomization to either ECT or IV ketamine group.
3. Men and women aged between 18 and 70 years, inclusive with a body mass index (BMI) \< 35. They must have a Montreal Cognitive Assessment (MOCA) score ≥ 24.
4. Patients meeting criteria for Major Depressive Disorder (MDD) or Bipolar Disorder (BP) without psychotic symptoms according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) currently in a Major Depressive Episode (MDE) as confirmed by the MINI International Neuropsychiatric Interview (MINI).
5. A Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 26 at screening and at randomization, with no more than 20% improvement between these two visits.
6. Female subjects of childbearing potential must have a negative urine pregnancy test at enrolment (Visit 1) and be willing to use a reliable method of birth control (i.e., double-barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device, or tubal ligation) during the study.
7. Abstain from consuming grapefruit juice (a potent 3A4 cytochrome inhibitor) on the day of the ketamine infusions as it may slow down the elimination of ketamine.
8. Be able to understand and comply with the requirements of the study, as judged by the investigator(s).

Exclusion Criteria:

1. Depression secondary to stroke, cancer or other severe medical illnesses.
2. Prior or current substance abuse or dependence (except for caffeine or nicotine dependence) and/or recent history (last 12 months) of current alcohol abuse or dependence, as defined in DSM-5 criteria ("a problematic pattern of using alcohol or another substance that results in impairment in daily life or noticeable distress").
3. A positive toxicology screen for drugs that are not prescribed.
4. Unwilling to maintain current antidepressant regimen.
5. Unwilling or unable to hold benzodiazepines from the evening prior to the infusion of ketamine.
6. Unwilling to discontinue any narcotic for a minimum of 5 drug half-lives prior to injections.
7. Pregnant, lactating, or of childbearing potential and not willing to use an approved method of contraception during the study.
8. Evidence of clinically relevant disease, e.g., uncontrolled hypertension, renal or hepatic impairment, significant coronary artery disease (myocardial infarct within a year prior to initial randomization), cerebrovascular disease, history of cerebrovascular accident, viral hepatitis B or C, acquired immunodeficiency syndrome.
9. A clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina).
10. Liver function tests AST and ALT three times the upper normal limit at screening.
11. Uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment (Visit 1).
12. Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator(s). Including:

    * Sodium under 135 or over 145 mmol/L
    * Potassium under 3.5 or over 5.0 mmol/L
    * Chloride under 98 or over 106 mmol/L
    * ALT under 17 or over 63 U/L
    * AST under 18 or over 40 U/L
    * Total bilirubin over 26 mmol/L
    * GGT under 9 or over 48 U/L
    * Fasting glucose under 3.3 or over 5.8 mmol/L
    * BUN under 2.5 or over 8.0 mmol/L
    * Creatinine under 50 or over 90 mmol/L in females, and under 70 or over 120 mmol/L in males
    * TSH under 0.4 or over 5.0 mU/L
    * CBC indicating:
    * Hemoglobin under 123 or over 157 g/L in females, and under 130 or over 170 g/L in males
    * Hematocrit under 0.370 or over 0.460 in females, and under 0.380 or over 0.50 in males
    * RBC under 4.0 or over 5.2x1012/L in females and under 4.4 or over 5.7x1012/L in males
    * MCV under 80 or over 100 fL
    * WBC under 4 or over 10x109/L
    * Neutrophil over 0.7x109/L
    * Lymphocyte under 1.0 or over 4.0x109/L
    * Monocyte under 0.1 or over 1.0x109/L
    * Eosinophil over 0.45x109/L
    * Basophils over 0.10x109/L
    * Platelets under 130 or over 400x109/L
13. ECG results considered clinically significant as determined by the investigator(s), or outside of normal range as per cardiologist analysis.
14. History of seizure disorder, except febrile convulsions.
15. Known history of intolerance or hypersensitivity to ketamine.
16. Any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measure.

Note: active suicidal intent in MDD with the absence of psychotic symptoms is not an exclusion criterion).
D: Inclusion Criteria:

* diagnosis of major depressive disorder consistent with DSM-IV-TR
* current episode greater than 8 weeks in duration
* Hamilton Depression score \>/- 21
* less than 25% reduction in depression during current episode assessed by ATRQ

Exclusion Criteria:

* Axis diagnosis of other psychiatric disorders
* Experiencing hallucinations, delusions, other psychotic symptomatology
* ECT during current episode

Answer: B