Please select the eligibility criteria that correspond to the clinical trial below.
Title: Optimization of Intravenous Ketamine for Treatment-Resistant Depression: A Randomized, Placebo-Controlled, Triple-masked, Clinical Trial
Brief Summary: Existing treatments for major depressive disorder (MDD) generally take weeks to months to exert their maximal benefit. There is an urgent need to develop rapid-acting treatments for MDD. Ketamine, a high-affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric and adult patients. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine may have rapid antidepressant properties for patients with severe mood disorders.

In this study we are investigating whether ketamine can have an antidepressant effect compared to midazolam. Midazolam has similar anesthetic effects compared to ketamine but has not been shown to be an antidepressant, and is therefore acting as an active control in this study.

The study period can last up to 8 weeks, depending on your response to the study medication. There are two required overnight stays in our Research Commons as part of this study.


Options:
A: 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.
B: 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
C: Inclusion Criteria:

* Diagnosis of Depression
* Inadequate response to an adequate course of antidepressants

Exclusion Criteria:

* Psychiatric disorder other than depression
* Pregnancy or lactation
* Current diagnosis of cancer
D: Inclusion Criteria:

1. Male or female patients, 21-80 years of age;
2. Female individuals who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative serum beta-human growth hormone at screening and at pre-infusion;
3. Participants must fulfill DSM-IV criteria for Major Depression without psychotic features, based on clinical assessment by a study psychiatrist and confirmed by a structured diagnostic interview, the Structured Clinical Interview for DSM-IV TR Axis I Disorders, Patient Edition (SCID-P);
4. Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration);
5. Participants have not responded to three or more adequate trials of an antidepressant as determined by Antidepressant Treatment History Form (ATHF) criteria (score \>=3);
6. Participant scores on the IDS-C30 must be greater than or equal to 32 at both Screening and within 24 hours prior to Visit 1a (Phase 1);
7. Current major depressive episode is of at least 4 weeks duration.
8. Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document;
9. Each participant must be able to identify a family member, physician, or friend who will participate in the Treatment Contract.

Exclusion Criteria:

1. Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder
2. Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;
3. Current diagnosis of Obsessive Compulsive Disorder or eating disorder (bulimia nervosa or anorexia nervosa);
4. Subjects with DSM-IV drug or alcohol abuse/dependence within the preceding 2 years;
5. Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation;
6. Patients judged clinically to be at serious and imminent suicidal or homicidal risk;
7. Women who are either pregnant or nursing;
8. Serious, unstable medical illnesses including hepatic, renal, gastroenterologic (including gastroesophageal reflux disease), respiratory (including obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics), cardiovascular (including ischemic heart disease and uncontrolled hypertension), endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
9. Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;
10. Patients with one or more seizures without a clear and resolved etiology;
11. Patients starting hormonal treatment (e.g., estrogen) in the last 3 months prior to Visit 1a;
12. Treatment with an irreversible MAOI or any other FDA approved Anti depressant medication within one week prior to Visit 1a (with the exception of a stable dose of non-benzodiazepines hypnotics i.e. zolpidem, eszopiclone, etc for at least 3 months);
13. Treatment with fluoxetine within 4 weeks prior to Visit 1a;
14. Evidence-based individual psychotherapy (e.g. CBT or IPT) and other non-pharmacological antidepressant treatments (e.g. light therapy) will not be permitted during the acute study period (7 day);
15. Previous recreational use of PCP or Ketamine.
16. Past intolerance or hypersensitivity to midazolam
17. Hypertension (systolic BP \>160 mm Hg or diastolic BP \>90 mm Hg) not controlled by diuretic or beta-blocker therapy alone or in combination.
18. Evidence of age-related cognitive decline or mild dementia suggested by a score of \< 27 on the Mini-Mental State Examination (MMSE) at Screening

Answer: D