Glutamatergic Adaptation to Stress as a Mechanism for Anhedonia and Treatment Response With Ketamine

Inclusion Criteria: MDD Patients: * willing and able to give written informed consent * men or women, 18-65 years of age * primary diagnosis of DSM-V MDD, current, as diagnosed by the SCID-I * score of ≥20 on the Beck Depression Inventory, which will include patients characterized as having "moderate/severe" (20-28) or "very-severe" (29-63) depressive symptoms * off all antidepressant therapy for at least 8 weeks prior to the baseline visit Healthy Controls: * willing and able to give written informed consent * men or women, 18-65 years of age Exclusion Criteria: MDD Patients: * history of any bipolar disorder or psychotic disorder * active psychotic symptoms of any type * substance abuse/dependence within 6 months of study entry (as determined by SCID) * unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination and laboratory testing), including upper respiratory disease or asthma, glaucoma or porphyria. * active suicidal ideation as determined by a score ≥3 on the Columbia Suicide Severity Rating Scale (C-SSR) * use of any recreational drugs as confirmed by urine drug screen at the time of scanning * pregnancy or lactation * use of glucocorticoids at any time during the study * Raynaud's disease that may interfere with the cold-pressor * contraindications for MRI * MMSE score \<28 * elevated blood pressure prior to infusion (systolic \> 160 or diastolic \>100) * history of treatment resistance as determined by ATRQ * prior adverse reaction to ketamine * use of antipsychotic medications * use of greater than 2mg daily of lorazepam or similar benzodiazipine. * Regular smoker as self-reported Healthy Controls: * evidence of any psychiatric disorder with exception of specific phobia, and no history of any psychiatric disorder except mild past substance use disorder as diagnosed by the SCID-I * history of any substance abuse within the last 6 months * use of any recreational drugs as confirmed by urine drug screen at the time of scanning * pregnancy or lactation * use of glucocorticoids at any time during the study * Raynaud's disease that may interfere with the cold-pressor * contraindications for MRI * MMSE score \<28 * Regular smoker as self-reported