Inclusion Criteria:

1. Age 18-65, male or female, any race/ethnicity
2. Mayo Clinic Depression Center inpatient or outpatient
3. Ability to provide informed consent
4. SCID confirmed major depressive episode associated with Major Depressive Disorder, Bipolar I/II disorder, or Schizoaffective Bipolar Disorder
5. Current index episode of major depression < 2 years duration
6. Moderate symptom severity defined by HAMD-17 rating scale score ≥ 17 [8]
7. Current index episode inadequately responsive to treatment (IRT). IRT defined as intolerability, adverse event, or inadequate efficacy of current psychotropic medications (at least 4 weeks duration)
8. Agree to abide by the study protocol and its restrictions and be able to complete all aspects of the study, including all visits and tests
9. Negative serum or urine pregnancy test (or history of hysterectomy)
10. Negative urine toxicology test (will only be completed at the request of the treating clinician).

Exclusion Criteria:

1. Inability to speak English
2. Inability or lack of willingness to provide informed consent
3. Axis I or II disorder other than depression (i.e., by clinical assessment) that is the primary reason for treatment
4. Psychotropic medication change (including dosage) between screening & baseline visit with exception of no more than 8mg of Ativan within a 24-hour period.
5. Patients who meet DSM-IV-TR criteria for any significant current substance use disorder other than nicotine, caffeine, or cannabis. Must have at least early, partial or full, remission X 3 months
6. Current clinical diagnosis delirium, dementia, other cognitive disorders, or non-mood psychotic disorder (i.e., schizophrenia, delusional disorder)
7. Index episode symptoms of hallucinations or delusions
8. Serious suicidal risk and/or in need of immediate hospitalization as judged by the investigator
9. History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 6 months
10. Significant unstable medical condition
11. Hepatic insufficiency (2.5 X ULN for AST or ALT), past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver
12. Malignancy (except basal cell carcinoma) and/or chemotherapy within 1 year prior to screening; malignancy more than 1 year prior to screening must have been local and without metastasis and/or recurrence, and if treated with chemotherapy, without nervous system complications
13. Participation in another clinical trial within 30 days of the screening visit
14. Anticipated inability to attend scheduled study visits
15. Patients who in the judgment of the Investigator may be unreliable or uncooperative with the evaluation procedure outlined in this protocol
16. Known cytochrome (CYP) & serotonin transporter genomic testing results within 5 years
17. A score of ≥15 on the YMRS