Ketamine Treatment Effects on Synaptic Plasticity in Depression

Inclusion Criteria: * Unipolar, major depressive episode (MDE), with 17-item Hamilton Depression Rating Scale score ≥16. Patients may be psychiatric medication- free, or if currently taking psychiatric medication, not responding adequately as evidenced by current MDE. * 18-55 years old * Female patients of child-bearing potential must be willing to use an acceptable form of birth control during study participation such as condoms, diaphragm, oral contraceptive pills. * Must be enrolled in division's umbrella research protocol * Able to provide informed consent * Agrees to voluntary admission to an inpatient research unit at The New York State Psychiatric Institute (NYSPI) for baseline PET imaging and Magnetic Resonance Imaging (MRI), ketamine infusion, and repeat PET imaging Exclusion Criteria: * Unstable medical or neurological illness including: A) baseline hypertension (BP\>140/90); B) significant history of cardiovascular illness; C) Platelet count \< 80,000 cells/uL; and D) Hemoglobin \< 11 g/dL for females and \< 12 g/dL for males * Significant electrocardiogram (ECG) abnormality (e.g., Ventricular tachycardia, evidence of myocardial ischemia, symptomatic bradycardia, unstable tachycardia, second degree (or greater) atrioventricular (AV) block). * Pregnancy, currently lactating, or planning to conceive during the course of study participation. * Diagnosis of bipolar disorder or current psychotic symptoms. * Current or past ketamine use disorder (lifetime); any drug or alcohol use disorder within past 6 months * Inadequate understanding of English. * Prior ineffective trial of or adverse reaction to ketamine. * A neurological disease or prior head trauma with evidence of cognitive impairment. Subjects who endorse a history of prior head trauma and score ≥ 1.5 standard deviations below the mean on the Trailmaking A\&B will be excluded from study participation. \- Metal implants or paramagnetic objects contained within the body (including heart pacemaker, shrapnel, or surgical prostheses) which may present a risk to the subject or interfere with the MRI scan, according to the guidelines set forth in the following reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic objects," F.G. Shellock, Lippincott Williams and Wilkins NY 2001. Additionally transdermal patches will be removed during the MR study at the discretion of the investigator. * Current, past, or anticipated exposure to radiation, that may include: \*\* * being badged for radiation exposure in the workplace * participation in nuclear medicine research protocols in the last year * Claustrophobia significant enough to interfere with MRI scanning * Weight that exceeds 325 lbs or inability to fit into MRI scanner * Individuals taking prescribed opioid medication, using opioids recreationally, or taking naltrexone at the time of enrollment 14. Daily use of: benzodiazepine, zolpidem (Ambien), zaleplon (Sonata), or eszopiclone (Lunesta) for ≥2 weeks at time of consent