Inclusion Criteria:
* DSM5 unipolar major depressive episode
* Persons of child-bearing potential must agree to use an acceptable method of birth control throughout the study.
Exclusion Criteria:
* Current or past ketamine abuse or dependence ever (lifetime)
* Any medical contraindication to ketamine, including prior ineffective trial of or medically significant adverse reaction to ketamine.
* Clinically significant EKG abnormality in terms of ketamine administration (e.g., Ventricular tachycardia, evidence of myocardial ischemia, symptomatic bradycardia, unstable tachycardia, second degree (or greater) AV block).
* Lifetime schizophrenia, schizoaffective illness, bipolar disorder, current psychotic depression; mild drug or alcohol use disorder in past 2 months; moderate or severe drug or alcohol use disorder in past 6 months; suicidal ideation with plan and/or intent within 6 months; suicide attempt in the past month.
* A first-degree family history of schizophrenia if the subject is less than 33 years old (mean age of onset for schizophrenia plus two standard deviations).
* Current or recent use of antidepressants within 14 days or benzodiazepines within 1 day. Use of fluoxetine or other long-acting antidepressant within 6 weeks.
* Current or recent use of medications known to affect brain biology of interest such as competing for binding sites of PET tracer within 1 month.
* Uncontrolled moderate or severe hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic\[41\]), history of Raynaud's phenomenon, seizures, an open cut, sore, or bone fracture on or near the hands to be used for the cold pressor test.
* Use of more than incidental NSAIDs (including aspirin), anti-inflammatories, immune suppressants or other pain medications.
* Significant active physical illness, particularly if it may affect the brain biology being studied; including chronic pain syndrome and medically compromising eating disorders or epilepsy.
* Lacks capacity to consent
* Aggressive behavior that is a significant threat to others such as physically assaultive behavior (in the last month).
* Pregnancy, abortion or miscarriage in the previous two months or plans to conceive during the course of study participation.
* Currently lactating
* Previous head injury with evidence of cognitive impairment. Subjects who endorse a history of prior head trauma and score 1.5 standard deviations below the mean on Trail-making A or B will be excluded from study participation.
* Any condition or material in the body that is a contraindication for MRI procedures.
* Current, past or anticipated exposure to radiation except if the exposure was at our PET center where the precise exposure is known
* ECT within past 6 months
* For A-Line Subjects: Unstable relevant medical condition (i.e., condition not adequately stabilized for 3 months). Including bleeding disorders, the need to take medications that affect blood clotting, and certain platelet and hemoglobin cutoffs
* Blind or with visual impairment that cannot be corrected with corrective lenses (glasses or contact lenses)
* No emergency contact
