Pilot Study: Establishing Glutamatergic Changes in Rapid Antidepressant Effects of Ketamine

Inclusion Criteria: 1. Age between 25 and 65 years; 2. Current depression as assessed on the SCID; 3. Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode. Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks 4. Able to comprehend English, as all questionnaires are in this language 5. Ability to provide informed consent Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria. Exclusion Criteria: 1. A sleep disorder other than insomnia, as determined by history; 2. History of bipolar disorder, delirium, dementia, amnestic disorder, schizophrenia and other psychotic disorders as assessed on the SCID; 3. Alcohol or drug abuse in the past year based upon the SCID or urine toxicology screen; 4. A current smoker; 4\) Any significant medical or neurological illness that impacts brain function or impedes participation; 5) History of head trauma with significant loss of consciousness; 6) Metallic implants, pacemakers or tattoos, or other contraindications to MRI; Claustrophobic, or intolerant of the scanner environment; 7) For women, pregnancy will exclude participation. 8) Untreated hypertension Based on ketamine's known difficulties with induction of perceptual/psychomimetic symptoms, exclusion criteria for this study are as follows: 1. Patients with a BMI over 40. 2. Ongoing prescription of 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment; 3. Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression; 4. Use of any MAOI is prohibited two weeks prior to administration of study drug; if patients are on an MAOI when enrolled, study drug will not be administered until two weeks off MAOI; 5. CYP3A4 inducers carbamazepine and modafinil are prohibited two weeks prior to administration of study drug and at least 24 hours after last dose of study drug. 6. Current use of Naltrexone; 7. Developmental delay, mental retardation, or intellectual disorder; 8. Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months; 9. Prior participation in another study of ketamine for depression 10. Prior treatment and/or recreational use of ketamine