This is a prospective open-label observational study of patients with treatment resistant bipolar depression referred for intravenous ketamine, with an interventional component of fMRI.

This is a prospective open-label observational study of patients with treatment resistant bipolar depression referred for intravenous ketamine. All participants will receive an acute series of ketamine consisting of twice weekly infusions over three weeks. Non-responders will have their End of Study visits within 5 days of the last ketamine infusion. Responders (participants who achieve a greater than or equal to 50% decrease on their QIDS-SR-16 score from Baseline) will return for three weeks of continuation treatment (weekly ketamine) and then have their End of Study visit within 5 days of the last continuation treatment. All participants will undergo fMRI the prior to their first ketamine infusion, and after completion of their acute series.

Inclusion Criteria:

1. Written informed consent before any study related procedures are performed

2. Males/females at least 18 years of age but no older than 75 years of age

3. Meet DSM-5 criteria for a current Major Depressive Episode and lifetime Bipolar I disorder or Bipolar II disorder as determined by both:

   A. a clinician's diagnostic evaluation and B. confirmed with the MINI International Neuropsychiatric Interview (MINI 7.0.2)

4. A current depressive episode that has lasted a minimum of 4 weeks as determined by both:

   A. a clinician's diagnostic evaluation and B. confirmed with the MINI International Neuropsychiatric Interview (MINI 7.0.2)

5. Meet all the following criteria on symptom rating scales at screening:

   A. Montgomery Asberg Depression Rating Scale (MADRS) score ≥20 B. Young Mania Rating Scale (YMRS) score of ≤ 5 C. QIDS-SR-16 score of ≥ 11

6. Have had ≥ 2 adequate trials of mood stabilizers, antipsychotics (only those FDA approved for bipolar depression), or antidepressants or augmentation strategies during their lifetime. An adequate trial is defined as 4 weeks of medication at the minimum FDA approved dose.

7. In the opinion of the investigator, the patient is willing and able to comply with scheduled visits, treatment plan, and other trial procedures for the duration of the study.

Exclusion Criteria:

1. Meet DSM-5 criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, or pervasive developmental disorder

2. Meets any exclusion criteria for ketamine treatment (uncontrolled arterial hypertension, uncontrolled hyperthyroidism, severe ischemic heart disease or heart failure, severe liver or kidney disease, space occupying lesion in the brain or the spinal cord, and uncontrolled glaucoma)

3. The patient is pregnant or breast feeding

4. The patient has a severe medical illness or severe neurological disorder

5. The patient has a known ketamine allergy or is taking a medication that may significantly interact with ketamine (see Appendix)

6. Diagnosis of psychotic features during the current depressive episode or within the past 6 months

7. Was previously enrolled in the trial

8. Active moderate or severe substance use disorder within the last 3 months (no exclusion for tobacco use disorder of any severity)

9. Current episode of mania/hypomania or mixed episode according to MINI or study clinician

10. MRI contraindications

    • Severe head trauma
    • Claustrophobia incompatible with scanning
    • Cardiac pacemaker
    • Implanted cardiac defibrillator
    • Aneurysm brain clip
    • Inner ear implant
    • Prior history as a metal worker and/or certain metallic objects in the body -- must complete MRI screening form and be approved by MRI technologist before each scan
    • History of clinically significant vertigo middle ear disorder, or double vision