The proposed study is a single-site, randomized, controlled clinical trial (RCT) comparing ketamine-assisted psychotherapy (KAP) to a standard evidence-based regimen of ketamine administered in a medical model without psychotherapy (KET). Eligible study participants will be adults with major depressive disorder (MDD). Adults with MDD will be randomized to KAP or KET in a 1:1 allocation. Each treatment group will receive KAP or KET over a period of four weeks. Measurement of depression severity, wellness, neurocognitive functioning and other parameters will occur at baseline prior to treatment, immediately following the end of the acute treatment period, and over an 8-week (two month) treatment follow-up period.

Inclusion Criteria

• Written informed consent (and assent when applicable) obtained from subject and ability for subject to comply with the requirements of the study.
• Age 18-90 years
• Participant in good physical health
• Participants may be on medications for depression as long as they remain on a stable dose.
• A score of at least 20 on the 10 item Montgomery-Asberg Depression Scale at screening, corresponding to at least moderate current depression severity.
• Meets criteria for major depressive disorder (MDD) in current major depressive episode (MDE) according to DSM-5
• Women of child-bearing potential must have a negative pregnancy test at screening and prior to ketamine infusion

Exclusion Criteria

• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• Any unstable medical illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease and uncontrolled hypertension); endocrinologic, neurologic, immunologic, or hematologic disease
• Clinically significant abnormalities of laboratories, physical examination, or ECG
• Substance drug or alcohol use disorder in the prior 12 months
• History of hypersensitivity to ketamine or esketamine
• Lifetime history of schizophrenia, schizoaffective disorder, bipolar I or II disorder
• Presence of psychotic symptoms in the current MDE, or lifetime psychotic disorder
• Recreational ketamine or phencyclidine use in the last year
• Previous non-response to clinical or research ketamine or esketamine administration
• Concurrent treatment with ECT, TMS, or VNS in the current MDE
• BMI > 35
• Significant suicidal ideation as determined by a C-SSRS score >2 in past 30 days
• History of suicide attempt or self harm in the prior 2 years
• SBP > 165 or DBP > 95 on infusion day
• MoCA score < 23

This is a study funded by private philanthropy and therefore we do not plan to share the results from the data.