Please select the eligibility criteria that correspond to the clinical trial below.
Title: Double-Blind, Cross-Over Trial of Ketamine Therapy Plus or Minus Naltrexone in Treatment Resistant Depression (TRD)
Brief Summary: The primary objective is to determine if the opioid properties of ketamine are responsible for its antidepressant effects. Since naltrexone can block opiate actions, the investigators will determine if naltrexone can effectively block ketamine's effects.


Options:
A: Inclusion Criteria:

* Aged 18-55 years
* Fulfilled the DSM-IV criteria of major depressive disorder
* Had a 17-item Hamilton Rating Scale for Depression (HAMD-17)\>or= 18
* No DSM-IV diagnosis of substance abuse or dependence (including alcohol) within the past 6 months
* Had been drug free for \> 3 months
* Physically healthy and had all laboratory parameters within normal limits.
* Agree to participate in the study and provide informed consent

Exclusion Criteria:

* Had history of epilepsy, head trauma or other major neurological or medical diseases
* Had psychotic depression, bipolar I/II disorder, schizophrenia or any other psychotic disorder
* Moderate-severe suicidal risks
* Severe cognitive impairment
* Female subjects who were pregnant, or at risk of pregnancy or lactation
* Initiating or stopping formal psychotherapy within six weeks prior to enrollment
* Had a history of poor response to SSRIs or previously received electroconvulsive therapy
* Had a history of severe adverse reaction to SSRIs.
B: Inclusion Criteria:

A subject will be eligible for inclusion only if all of the following criteria are met:

1. Male or female, 18 to 70 years of age, inclusive, at screening.
2. Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information.
3. 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, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR™). The diagnosis of MDD will be made by a site psychiatrist and supported by the Structured Clinical Interview for DSM-IV-TR™ (SCID-I/P) or the M.I.N.I International Neuropsychiatric Interview a short, structured psychiatric interview.
4. Has a history of TRD during the current MDE, as assessed by the investigator. TRD is defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms), as perceived by the participant, to at least two "treatment courses" of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration. The adequacy of dose and duration of the antidepressant therapy will be determined as per the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) criteria. Participants must currently be on a stable (for at least 4 weeks) and adequate (according to the MGH ATRQ) dose of ongoing Selective serotonin reuptake inhibitor (SSRI) or Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant therapy, of which total duration must be at least 8 weeks. Participants may also have a history of intolerance to at least 2 antidepressant medications. These patients with the intolerance history will not be required to be currently taking an antidepressant medication.
5. Meet the threshold on the total Hamilton Depression 17-item Scale (HAMD17) score of \>/=20 at both screening and baseline visits (Day -5/-14 and Day 0).
6. In good general health, as ascertained by medical history, physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, and 12-lead electrocardiogram (ECG).
7. If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:

   1. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or
   2. Childbearing potential, and meets the following criteria:

   i. Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.

   ii.Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment.

   iii.Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and baseline.
8. Body mass index between 18-35kg/m2.
9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented, et al) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject's participation in the study.
10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, or trazodone) 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:

A potential participant will NOT be eligible for participation in this study if any of the following criteria are met:

1. Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
2. Female that is pregnant or breastfeeding.
3. Female with a positive pregnancy test at screening or baseline.
4. Total HAMD score of \<20 at the screen or baseline visits.

6. Current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, at screening or within six months prior to screening.

7. Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past six months or more).

8. History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes.

9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within five years of screening.

10. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening.

11. Considered at significant risk for suicide during the course of the study according to any of the following criteria:

12. In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the study.

13. Has dementia, delirium, amnestic, or any other cognitive disorder.

14. Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results.

15. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation.

16. Known history or current episode of:

a. QTcF (a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle-Fridericia-corrected) ≥450 msec at screening (Visit 1) or randomization b. Syncopal event within the past year. c. Congestive heart failure (CHF) New York Heart Association Criteria \>Stage 2 d. Angina pectoris e. Heart rate \<50 or \>105 beats per minute at screening or randomization

17. Chronic lung disease.

18. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or a history of significant head trauma within the past two years.

19. Presents with any of the following lab abnormalities w/in the past 6 months:

1. Thyroid stimulating hormone (TSH) 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. Any other clinically significant abnormal laboratory result at the time of the screening exam.

   20. History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than six months prior to screening.(Subjects on a stable dosage of thyroid replacement medication for at least six months or more prior to screening are eligible for enrollment.)

   21. History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening.

   22. 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.

   23. History of positive screening urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, opiates.

   24. Chronic use of opiates.
C: Inclusion Criteria:

* Male or female patients between 18 and 85 years of age at screening.
* Patients must provide written informed consent prior to study entry.
* Patients must meet DSM-IV-TR (Diagnostic and Statistical Manual IV Text Revision) criteria for Major Depressive Episode of a severity mild, moderate or severe or in partial remission, as confirmed by the MINI.
* Patients must have a HAM-D (17-item) score of 16 or higher.
* Patients must have been on 1 of the following medications for 4 or more weeks at or above the listed dose with no psychiatric medication dose changes for the past 25 days:

  * 20 mg qD of fluoxetine (Once Daily)
  * 50 mg qD of sertraline
  * 20 mg qD of paroxetine
  * 200 mg qD of fluvoxamine
  * 20 mg qD of citalopram
  * 10 mg qD of escitalopram
  * 150 mg qD of venlafaxine or venlafaxine sustained release
  * 300 mg qD of bupropion or bupropion sustained or extended release
  * 15 mg qD of mirtazapine
  * 60 mg qD of duloxetine
* Participants must agree to keep the dose of their existing antidepressant(s) constant throughout the 8-week trial.

Exclusion Criteria:

* Diagnosis of bipolar disorder or schizophrenic or schizoaffective disorder.
* History of alcohol or drug abuse or dependence within 6 months of enrollment.
* Patients who have received ECT (Electroconvulsive Therapy) in the past 3 months.
* History of seizures.
* Moderate dementia (MMSE score of 20 or less).
* Active suicidal ideation: endorsing a 3 (most severe score) on QIDS-SR (Quick Inventory of Depression Symptomatology Self Reports) suicide item OR a score of 2 or higher for the past week on Suicide Scale items 4 or 5 (current suicidal ideation moderate or strong or would avoid taking steps to save life).
* Currently taking a mood stabilizer or antipsychotic (except lithium clearly used as an augmenting agent).
* Patients who, in the opinion of the investigator, might not be suitable for the study.
D: 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

Answer: B