Please select the eligibility criteria that correspond to the clinical trial below.
Title: N-methyl-D-aspartate Receptor (NMDAR)-Based Pharmacotherapy With D-cycloserine for Treatment-resistant Major Depressive Disorder
Brief Summary: For many depression patients treatment changes are required, including switching to another antidepressant and addition of a second antidepressant or a non-antidepressant agent ("augmentation"). The need to modify treatment is usually necessary because of partial or no response to first-line monotherapy or the failure to achieve remission although treatment response (improvement) has been obtained. These caveats of presently available antidepressant drugs highlight the need for innovative pharmacological treatment strategies. Recent data suggest that N-methyl-D-aspartate receptor (NMDAR) antagonists and partial agonists at the NMDAR-associated glycine binding site may represent a novel type of antidepressant medications. These types of compounds protect vulnerable neurons against a variety of insults, including stress-induced damage, and may serve to enhance and maintain normal synaptic connectivity. In animal models, these compounds mimic the effects of clinically effective antidepressants. Furthermore, down-regulation of the glycine site of the NMDAR was found to be a common feature of currently used antidepressant medications. D-cycloserine (DCS , Seromycin) is a broad spectrum antibiotic, in use for over thirty years against tuberculosis, that acts as a partial agonist at the NMDAR-associated glycine site. Beneficial antidepressant effects have been reported with 500-1000 mg/day DCS regimens in depressed tuberculosis patients and recent preliminary findings suggest that DCS may also be beneficial in the treatment of major depressive disorder. The antidepressant effects of DCS seem to reflect consequences of its capacity to reduce NMDAR receptor function. In the present project, it is proposed to assess, using a random assignment, parallel-group, double blind, placebo controlled design, the effects of a NMDAR -antagonist DCS dose regimen, 250 --\> 1000 mg/day for 6 wks, as adjuvant pharmacotherapy for treatment-resistant major depressive disorder patients. The study methodology includes the assessment of DCS effects upon symptoms profile, neurocognitive tests performance, amino acids serum levels, and brain electrophysiology parameters associated with the prepulse inhibition-startle response paradigm. It is hypothesized that significant beneficial DCS treatment effects will be registered.


Options:
A: Inclusion Criteria:

* DSM-IV diagnosis of major depression .
* HAMD scale score of ≥20 despite at least two adequate antidepressant treatment trials during the current episode.

Exclusion Criteria:

* Underwent ECT treatment during the 3 months preceding the study.
* Change in psychotropic medications doses during the 3 weeks preceding the study.
* Concurrent unstable medical or neurological illness.
* Patients are judged to be potentially violent towards themselves or others, or have a history of drug/alcohol abuse.
B: Inclusion Criteria:

* outpatients or inpatients at the Puget Sound VA with diagnosis of major depressive disorder or bipolar 1 or 2 over the age of 18 undergoing index course ECT

Exclusion Criteria:

* uncontrolled hypertension (blood pressure \> 180/90 mmHg at the pre-anesthesia clinic visit)
* renal failure
* neurologic disorders (e.g. epilepsy, space occupying lesions, traumatic brain injuries in the past 6 months)
* myocardial infarction in the past 6 months
* known allergies or adverse reactions to ketamine
* American Society of Anesthesiology Physical Class greater than 3
* concomitant psychosis
* schizophrenia or current abuse of alcohol or illicit substances and pregnancy (any trimester)
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:

--Participant must meet Diagnostic and Statistical Manual of Mental Disorders -Fourth Edition -Text Revised (DSM-IV-TR) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment, and confirmed by the Mini International Neuropsychiatric Interview (MINI)-Participant's major depressive episode and treatment response must be deemed "valid" by remote independent raters-Participant must have had an inadequate response to at least 2 antidepressants, at least one of which is in the current episode of depression; the antidepressant treatment response questionnaire (ATRQ) will be used to assess antidepressant treatment response during the current episode; prior medication history will be used to determine antidepressant treatment response in prior episode(s) -Have an Inventory of Depressive Symptoms-Clinician rated, 30-item (IDS-C30) total score \>=34 at Screening and predose at Day 1

Exclusion Criteria:

-Participant has a current DSM-IV-TR diagnosis of bipolar and related disorders, intellectual disability, or cluster b personality disorder (e.g., borderline personality disorder, antisocial personality disorder, histrionic personality disorder, and narcissistic personality disorder) -Participant has a current or prior DSM-IV-TR diagnosis of a psychotic disorder, MDD with psychosis, post-traumatic stress disorder (PTSD), or obsessive compulsive disorder (OCD) -Anatomical or medical conditions that may impede delivery or absorption of study medication (e.g., undergone facial reconstruction, rhinoplasty, significant structural or functional abnormalities of the nose or upper airway; obstructions or mucosal lesions of the nostrils or nasal passages; undergone sinus surgery in the previous 2 years; signs and symptoms of rhinitis) -Has an abnormal or deviated nasal septum with any 1 or more of the following symptoms: blockage of 1 or both nostrils, nasal congestion (especially 1-sided), frequent nosebleeds, frequent sinus infections, and at times has facial pain, headaches, and postnasal drip -Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within the previous 1 year of the screening visit -Participant has known allergies, hypersensitivity, intolerance, or contraindication to esketamine/ketamine or its excipients

Answer: A