Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Parallel-group Study of the Safety and Efficacy of RO4917523 Versus Placebo, as Adjunctive Therapy in Patients With Major Depressive Disorder With Inadequate Response to Ongoing Antidepressant Treatment
Brief Summary: This randomized, double-blind, placebo-controlled, parallel group study will evaluate the safety and efficacy of RO4917523 as adjunctive therapy in patients with major depressive disorder and an inadequate response to ongoing antidepressant therapy. Anticipated time on study treatment is 6 weeks with a 3-week follow-up.


Options:
A: 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).
B: Inclusion Criteria:

* Adult patient, 18 to 70 years of age at time of informed consent
* Major depressive disorder without psychotic features as defined by DSM-IV-TR criteria
* Inadequate response to ongoing antidepressant treatment, as defined by protocol
* Body mass index (BMI) 18 to 38 kg/m2 inclusive

Exclusion Criteria:

* Currently receiving treatment with a combination of antidepressants (two or more), or an adjunctive potentiating treatment as defined by protocol
* Previously received RO4917523
* History of failure, or utilization during the current episode of Electroconvulsive Therapy (ECT) or repetitive Transcranial Magnetic Stimulation (rTMS)
* History of use at any time of Vagus Nerve Stimulation (VNS) or Deep Brain Stimulation (DBS)
* Current or past history of bipolar disorder (e.g. manic, hypomanic, or mixed episodes)
* Pregnant or lactating women
C: 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, participants must have had non-response (less 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 taken at adequate dosage and for adequate duration, as 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.

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 (i.e, 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 psychotic features bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, 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
D: Inclusion Criteria:

* clinical laboratory values \< 2x the upper limit of normal
* ability to understand the requirements of the study and provide informed consent

Exclusion Criteria:

* alcohol abuse
* abuse of illicit substances
* current smoker
* currently taking prescription medications (other than for birth control)
* history of allergy to NMDA receptor ligands
* received another investigational drug within 30 days
* psychiatric disease

Answer: B