Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicentre, Double-blind, Randomised, Placebo - Controlled Phase II Study to Assess Efficacy, Safety and Pharmacokinetics of Inhaled Esketamine in Subject With Treatment-resistant Bipolar Depression
Brief Summary: The purpose of the study is to determine the efficacy, safety and pharmacokinetics of inhaled Esketamine in participants with treatment-resistant bipolar depression (TRBD). The study is to determine the efficacy and dose response of three Esketamine doses, compared with placebo.


Options:
A: 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
B: Inclusion Criteria:

1. Gender: female or male,
2. Age: 18 - 65 years old, inclusive, on the day of Screening,
3. Participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for depressive episode in Bipolar Disorder (BD) type I or II, without psychotic features, confirmed by the Mini International Neuropsychiatric Interview (MINI),
4. Participant must have in Montgomery-Asberg Depression Rating Scale (MADRS) total score of \>= 24 at Screening and predose on Day 1,
5. Participant is treatment resistant in the current episode of depression, defined as having an inadequate response to at least 2 adequate mood stabilizing treatment regimens administered for the sufficient duration and dose and administered in the current episode of depression,
6. Participant in the last mood stabilizing treatment regimen is to be administered at least one of the medication listed in the protocol,
7. Participant's last mood stabilizing treatment regimen is to be without antidepressant drugs from the class: SSRI, SNRI, TCA, MAOI or NaSSA,
8. Participant must be on stable mood stabilizing treatment regimen (listed in the protocol), remain non-responsive to it and continue the treatment from Screening to at least the duration of the double-blind treatment phase,
9. Participant's other drugs taken as a standard treatment for bipolar disorder, but not for depressive episode treatment, are to be allowed and may be continued through the study and it's administration is up to Investigator discretion,
10. Participant agrees to be hospitalized voluntarily for a period of 12 h before first administration and until the end of treatment phase on Day 14,
11. Participant must be medically stable on the basis of clinical laboratory tests, physical examination, vital signs, 12-lead ECG,
12. Participant agrees to blood sample collection for DNA analysis,
13. Participant of childbearing potential willing to use acceptable forms of contraception.

Exclusion Criteria:

1. Participant has a current DSM-5 diagnosis, according to MINI, of any other than BD disorder,
2. Participant has a BD with a rapid-cycling course (≥ 4 episodes per year),
3. Participant has in Young Mania Rating Scale (YMRS) total score of greater than 12 at Screening and every other assessment,
4. Participant has suicidal ideation in MADRS 'suicidal thoughts' subscale score greater or equal to 2 and/or in C-SSRS score greater or equal to 4 at Screening and/or has a history of suicidal thoughts within 6 months prior to Screening and/or history of suicidal attempt within 1 year prior to Screening,
5. Participant has a history or current signs and symptoms of chronic obstructive pulmonary disease (COPD), asthma, liver or renal insufficiency, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, hematologic, neurologic, rheumatologic or metabolic disturbances that are uncontrolled with medication change during last three months before Screening and/or that could influence the present general health condition at the Investigator's discretion,
6. Participant has uncontrolled hypertension,
7. Upper respiratory tract and/or chest infection and/or inflammation within 2 weeks preceding the first administration and during the treatment phase,
8. Participant took part in other clinical trial within 90 days preceding the Screening,
9. Known allergy or hypersensitivity, intolerance or contraindication to Esketamine/ketamine or its derivatives and/or to any study product excipients,
10. Blood drawn within 30 days prior to inclusion to the study,
11. History of drug, alcohol, chemical, sedatives or sleeping medications abuse or dependence (except nicotine or caffeine) within 2 years prior to Screening,
12. Lifetime abuse or dependence on ketamine or phencyclidine,
13. Positive results from pregnancy test for female participants,
14. Lactation in female participants,
15. Positive drug screen (except benzodiazepines evaluation during follow-up) or alcohol breath test.
C: * INCLUSION CRITERIA:

General patient inclusion criteria

1. Male or female subjects, 18 to 65 years of age.
2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
3. Subjects must fulfill DSM-IV criteria for Major Depressive Disorder (MDD) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
4. Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.
5. Subjects must have failed to respond in the past to an adequate dose and duration of at least one antidepressant (SSRI, bupropion, or venlafaxine) during a depressive episode
6. Current depressive episode of at least 4 weeks duration.

Additional inclusion criteria for substudy 4 (patients with MDD)

1. Age of onset less than 40 years of age.
2. Subjects with MDD must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).
3. A failed adequate trial of ECT would count as an adequate antidepressant trial.
4. In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

Inclusion criteria for healthy control subjects (Substudy 4 only)

1. Age 18-65 years.
2. Written informed consent completed.

EXCLUSION CRITERIA:

General patient exclusion criteria

1. Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
2. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
3. Female subjects who are either pregnant or nursing.
4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
5. Subjects with uncorrected hypothyroidism or hyperthyroidism.
6. Subjects with one or more seizures without a clear and resolved etiology.
7. Treatment with a reversible MAOI within 4 weeks prior to study phase I.
8. Treatment with fluoxetine within 5 weeks prior to study phase I.
9. Treatment with any other concomitant medication not allowed (Appendix A for Substudy 2; Appendix G for Substudy 4) 14 days prior to study phase I.
10. No structured psychotherapy will be permitted during the study.
11. Current NIMH employee/staff or their immediate family member.

Additional Exclusion Criteria for substudy 2 (patients with MDD)

1. Previous treatment with ketamine or hypersensitivity to amantadine.

Additional Exclusion Criteria for Substudy 4 (patients with MDD)

1. Subjects who currently are using drugs (except for caffeine or nicotine), must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.
2. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
3. Clinically significant abnormal laboratory tests.
4. For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).
5. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of \>4.

Exclusion Criteria for healthy control subjects (Substudy 4 only)

1. Current or past Axis I diagnosis
2. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).
3. Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
4. Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4.
5. Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).
6. Presence of psychiatric disorders in first-degree relatives.
7. Female subjects who are either pregnant or nursing.

7.8.Current NIMH employee/staff or their immediate family member.
D: Inclusion Criteria:

* between the ages of 18 and 65 years old
* diagnosed with depression and being referred for ECT
* American Society of Anesthesiologists (ASA) score of 1 or 2
* patient receiving ECT on an informal basis (i.e. consenting to treatment and able to give informed consent)

Exclusion Criteria:

* pre-existing neurological disease or cognitive impairment
* co-morbid psychiatric diagnoses
* pre-existing hypertension
* severe respiratory tract disease
* major cardiovascular disease
* pacemakers
* cerebrovascular disorder or malformation
* intracranial mass lesions
* seizure disorder
* intracranial electrode or clips
* intra-ocular pathology
* endocrine or metabolic disease
* severe hematologic disease
* severe fracture
* not able to give consent
* pregnancy

Answer: B