Inclusion Criteria:
* Have given written informed consent
* Meet DSM-5 criteria for MDD
* MADRS \>= 28 at screening Can read, write, and speak English fluently
* Be judged by study team clinicians to be at low risk for suicidality
Exclusion Criteria:
* Women who are pregnant, nursing, or not practicing an effective means of birth control
* Cardiovascular conditions: hypertension with resting blood pressure systolic \>139 or diastolic \>89, angina, heart rate \> 99, a clinically significant ECG abnormality (e.g., atrial fibrillation, QTc \> 450), TIA in the last 6 months stroke, peripheral or pulmonary vascular disease, cardiac valvulopathy
* Epilepsy
* Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
* Currently taking antipsychotics, or MAO inhibitors
* Patients taking antidepressant medications and unable to taper
* Moderate or strong CYP2D6 inhibitor antidepressants must undergo a washout period of 4 weeks or five half-lives prior to treatment
* Currently taking CYP2D6 inhibitor other than an antidepressant that will be tapered
* Currently taking efavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse), Alcohol dehydrogenase inhibitors, or UGT1A9 inhibitors or UGT1A10 inhibitors such as phenytoin, regorafenib, eltrombopag
* Have a seizure disorder, multiple sclerosis, history of significant head trauma, CNS tumor, movement disorders or any neurodegenerative condition
* Morbidly obese (\>100 lbs. above ideal body weight, or BMI \>=40, or BMI \>=35 with high blood pressure or diabetes)
* Be judged by a study team clinician to be at risk for moderate or severe alcohol or benzodiazepine withdrawal
* Body weight \< 45 kg
* Significant acute adverse reaction (e.g., dystonia) to an antipsychotic
* Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (including substance-induced), Bipolar I or II Disorder or Major
* Depression with psychotic features
* Have a first degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or Bipolar I Disorder.
