Medically healthy Veterans ages 21-75 that have been diagnosed with Depression will get up to 6 treatments of Ketamine infusions, weekly. After treatment is completed, follow up will occur at 1 month, 3 months, and 6 months after completion of infusions to evaluate the longer term effects of ketamine.

A total of 25 depressed subjects between the ages of 21-75 who have current major depressive disorder without psychotic features by DSM-5 will be recruited. Subjects will be accepted into the protocol after an opportunity to review and provide voluntary written informed consent and completion of a comprehensive medical and psychiatric history, physical examination, mental status examination, and routine laboratory assessments. Patients will be recruited in outpatient settings to the Refractory Depression Clinic. Providers or Refractory Depression consult team will be informed if the patient may be eligible for participation in the ketamine protocol. Subjects must have established care in the VA Connecticut Healthcare System. If the Veteran is interested, a screening visit for further evaluation for the ketamine protocol will be scheduled. Veterans will receive up to 6 infusions for ketamine weekly, per PI discretion. The primary goal of this proposal is to test the effectiveness of repeated ketamine treatment (0.5 mg/kg; once or twice a week for up to 6 weeks; up to a total of 6 ketamine infusions). An open-label trial will be conducted that will include up to 25 Veterans with MDD with a follow-up of 6 months. This open-label trial will allow us to examine the safety and tolerability of the ketamine treatment in this population and the long-term effects. All patients will receive usual standard care during this trial.

Inclusion Criteria:

1. Male or female, 21-75 years old
2. Current major depressive disorder without psychotic features by DSM-5
3. Montgomery-Åsberg Depression Rating Scale (MADRS) ≥ 20
4. Able to provide written informed consent

Exclusion Criteria:

1. Current or past history of psychotic features or psychotic disorder
2. Current or past history of delirium or dementia
3. Current uncontrolled hypertension (systolic BP > 170 mm Hg or diastolic BP > 100 mm Hg)
4. Unstable medical condition or allergy to ketamine or lorazepam---clinically determined by a physician
5. Pregnant or nursing women, positive pregnancy test, or inadequate birth control methods in women of childbearing potential
6. Positive opioid or illicit drug screen test (except marijuana)

There is no plan to make IPD available to other researchers.