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