Endogenous Opioid Modulation by Ketamine

Inclusion Criteria:

* Age 18-65
* DSM-5 major depressive disorder
* Current moderate-to-severe, treatment-resistant, depressive episode
* Patient Health Questionnaire (PHQ-9) total score ≥ 10
* PHQ-9 item score ≥ 2 on "Little interest or pleasure" item
* PHQ-9 item score ≥ 2 on "Feeling down, depressed, or hopeless" item
* Medical documentation of depression for at least 2 months
* Inadequate response to at least one adequate antidepressant medication trial in the current episode

Exclusion Criteria:

* Current episode duration \>5 years
* Moderate-to-severe DSM-5 substance use disorder (past year)
* Cognitive disorder (past year)
* Post-traumatic stress disorder (past year)
* Obsessive compulsive disorder (past year)
* Personality disorder (past year)
* Positive urine drug screen
* Psychotic symptoms
* Mania
* Significant neurologic disorder or injury
* Breastfeeding or pregnancy
* Imminent suicide risk
* Current use of CYP3A4 inhibitors (e.g., ketoconazole or erythromycin)
* Other unstable psychiatric or medical condition requiring a higher level of care
* Contraindication to ketamine, MRI, or PET