Biomarkers of Response to Ketamine in Depression: MRI and Blood Assays Before and After Open Label Intranasal Ketamine

Inclusion Criteria:

1. Male or female, 18 to 65 years of age, inclusive, at screening.
2. Able to read, understand, and provide written, dated informed consent prior toscreening. Participants will be deemed likely to comply with study protocol andcommunicate with study personnel about adverse events and other clinically importantinformation.
3. Ability to participate in MRI (no history of claustrophobia, no presence of metallicforeign bodies incompatible with MRI, as assessed with MRI checklist and clinicalinterview).
4. Diagnosed with Major Depressive Disorders (MDD), single or recurrent, and currentlyexperiencing a major depressive episode (MDE) of at least eight weeks in duration,prior to screening, according to the criteria defined in the Diagnosis and StatisticalManual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of MDD will be madeby a site psychiatrist and supported by the Structured Clinical Interview for DSM-5 (SCID-5).
5. Has a history of treatment-resistant depression (TRD), as assessed by the investigatorusing the Mass General Hospital Antidepressant Treatment History Questionnaire (MGHATRQ). 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 1 "treatment course" of a therapeutic dose of an antidepressant therapy of at least 8weeks duration (including the current antidepressant treatment). The adequacy of doseand duration of the antidepressant therapy will be determined as per the MGH ATRQcriteria.
6. Depression is of at least "moderate" severity, as determined by a Clinical GlobalImpression-Severity scale (CGI-S) score greater than or equal to 4).
7. In good general health, as ascertained by medical history, physical examination (including measurement of vital signs), clinical laboratory evaluations, andelectrocardiogram (ECG).
8. If female, a status of non-childbearing potential or use of an acceptable form ofbirth control per the following specific criteria: a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant,i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), oris post-menopausal with her last menses at least one year prior to screening); or b.Childbearing potential, and meets the following criteria: i. Childbearing potential,including women using any form of hormonal birth control, on hormone replacementtherapy 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 issexually abstinent. ii. Negative urinary pregnancy test at screening, confirmed by a negative urinarypregnancy test at baseline, prior to receiving ketamine treatment. iii. Willing and able to continuously use one of the following methods of birthcontrol during the course of the study, defined as those which result in a low failurerate (i.e., less than 1% per year) when used consistently and correctly: implants,injectable or patch hormonal contraception, oral contraceptives, IUD, double-barriercontraception, sexual abstinence. The form of birth control will be documented atscreening and baseline.
9. Body mass index between 18-35 kg/m2.
10. Concurrent benzodiazepine therapy will be allowed if the dose is less than or equal to 2mg of lorazepam (or the equivalent) per day and stable for the past 4 weeks.

Exclusion Criteria:

1. Female of childbearing potential who is not willing to use one of the specified formsof birth control during the study.
2. Female that is pregnant or breastfeeding.
3. Female with a positive pregnancy test at screening or baseline.
4. Current diagnosis of a substance use disorder, except for nicotine dependence, atscreening or within 6 months prior to screening.
5. History of bipolar disorder, schizophrenia or schizoaffective disorders, or anyhistory of psychotic symptoms in the current or previous depressive episodes.
6. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwisespecified, within 5 years of screening.
7. In the judgment of the investigator, the subject is considered at significant risk forsuicidal behavior during his/her participation in the study.
8. Has dementia, delirium, amnestic, or any other cognitive disorder.
9. Has a clinically significant abnormality on the screening physical examination thatmight affect safety, study participation, or confound interpretation of study resultsaccording to the study clinician.
10. Current episode of:
11. Hypertension, Stage 1 as defined by a systolic blood pressure ≥160 mmHg ordiastolic blood pressure ≥100 mmHg at screening (Visit 1) or within 1.5 hoursprior to ketamine administration on two of three measurements (standing andsupine) at least 15 minutes apart.
12. Recent myocardial infarction (within one year) or a history of myocardialinfarction.
13. Syncopal event within the past year.
14. Congestive heart failure (CHF): New York Heart Association Criteria >Stage 2
15. Angina pectoris.
16. Heart rate <45 or >110 beats per minute at screening or Visit 3 ( first ketamineadministration).
17. QTcF (Fridericia-corrected) ≥450 msec at screening or Visit 3 (first ketamineadministration).
18. Chronic lung disease excluding asthma.
19. Lifetime history of surgical procedures involving the brain or meninges, encephalitis,meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's orParkinson's Disease), epilepsy, mental retardation, or any otherdisease/procedure/accident/intervention which, according to the screening clinician,is deemed associated with significant injury to or malfunction of the CNS, or historyof significant head trauma within the past 2 years.
20. Presents with any of the following lab abnormalities:
21. Thyroid stimulating hormone (TSH) outside of the normal limits and clinicallysignificant as determined by the investigator. Free thyroxine (T4) levels may bemeasured if TSH level is high. Subject will be excluded if T4 level is clinicallysignificant.
22. Patients with diabetes mellitus fulfilling any of the following criteria: i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% atscreening. ii. Admitted to hospital for treatment of diabetes mellitus or diabetesmellitus-related illness in the past 12 weeks. iii. Not under physician care for diabetes mellitus. iv. Has not been on the same doseof oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. Forthiazolidinediones (glitazones) this period should not be less than 8 weeks. c. Any other abnormal laboratory result(s), clinically significant in the opinion ofthe investigator, at the time of the screening.
23. History of hypothyroidism and has been on a stable dosage of thyroid replacementmedication for less than 2 months prior to screening. (Subjects on a stable dosage ofthyroid replacement medication for at least 2 months or more prior to screening areeligible for enrollment.)
24. History of hyperthyroidism which was treated (medically or surgically) less than 6months prior to screening.
25. History of positive screening urine test for drugs of abuse at screening: cannabinoids (if the patient has a legitimate medical prescription for cannabis, patient must agreeto abstain during the entirety of the study and to have a negative test at baseline),cocaine, amphetamines, barbiturates, opiates (unless use is in accordance withguidance provided in Appendix 1, table of allowed and excluded medications).
26. Patients with exclusionary laboratory values (see Table 1) or requiring treatment withexclusionary concomitant medications (see Appendix 1).
27. Patients with a history of narrow angle glaucoma.
28. Liver or renal Function Tests (LFTs) which meet the exclusion criteria in Table 1, ora history of hepatic or renal dysfunction.
29. Self-reported history of a ketamine or hallucinogen abuse or misuse. TABLE 1: EXCLUSIONARY SAFETY VALUES OF POTENTIAL CLINICAL CONCERN Hematology Leukocytes <2or >17.5 x 103/mm3 Platelets <75 or >700 x 103/mm3 Chemistry Total bilirubin >2 times theupper limit of the reference range AST* >2.5 times upper limit of the reference range ALT* >2.5 times upper limit of the reference range GGT* >2.5 times upper limit of the referencerange Alk Phosphatase* >2.5 times upper limit of the reference range Creatinine >1.3 timesupper limit of the reference range BUN/Urea >1.3 times upper limit of the reference rangeGlucose < 70 mg/dl or >2 times the limits of the reference range Uric acid >1.5 times upperlimit of the reference range

*LFTs higher than 2.5 times ULN will be exclusionary.