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