Endogenous Opioid Modulation by Ketamine

This study will test the hypothesis that the rapidly-acting antidepressant ketamine improves
core depressive symptoms by acutely activating the brain's endogenous µ-opioid system.

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