Funding ended.

Anxious depression is a particularly difficult-to-treat subtype of depression. Patients with anxious depression do not respond as well to currently available antidepressant medications. Nevertheless, in previous studies, low dose IV ketamine, which rapidly decreases symptoms of depression within hours in many patients with "treatment-resistant" depression, has been associated with superior efficacy in those individuals with anxious compared with non-anxious depression. In order to understand this unique effect more fully, the current protocol is aimed at further delineating biomarkers of ketamine's effects among individuals with treatment-resistant anxious depression compared to those with nonanxious depression.

Inclusion Criteria:

1. be 18-64 years old,
2. read, understand, and provide written informed consent in English,
3. meet criteria for a primary psychiatric diagnosis of Major Depressive Disorder (MDD) for ≥ 4 weeks,
4. have a history ≥1 failed medication trial during the current depression,
5. be on a stable adequate dose of an FDA-approved antidepressant medication for ≥28 days,
6. maintain a treating doctor who is in agreement with study participation,
7. have a reliable chaperone to accompany them home following the completion of the ketamine infusion day,
8. be generally healthy, as assessed by medical history, physical examination (including vital signs), clinical laboratory evaluations, and electrocardiogram (EKG),
9. be of non-childbearing potential or use of an acceptable form of birth control (females only).

Exclusion Criteria:

1. delirium or dementia diagnosis,
2. unstable medical illness or clinically significant laboratory results,
3. history of clinically significant cardiovascular disease or electrocardiogram (EKG) findings, or medical conditions that put the patient at risk for possible cardiac side effects (e.g., requirement of cardiac pacemaker) or alter brain morphology (e.g., recent head trauma, post intracranial surgery, intracranial mass or bleed or unstable sleep apnea), or a blood pressure >140/95 mmHg at Screening,
4. history of multiple adverse drug reactions,
5. current/past history of psychotic disorders, history of out-of-body feelings or derealization,
6. active substance use disorders (except nicotine and caffeine) within the past six months or past history of ketamine/PCP (phencyclidine) abuse (we will confirm this with collateral information from their doctor if necessary),
7. requirement of excluded medications that may interact with ketamine,
8. caffeine or nicotine use within 1 hour of psychophysiology testing, or alcohol use within 1 day of testing,
9. pregnancy, breastfeeding, or unacceptable means of birth control (females only)
10. clinically significant hearing impairment,
11. current serious suicidal or homicidal risk,
12. concurrent participation in other research studies involving medications or other treatments,
13. narrow angle glaucoma,
14. acute intermittent porphyria history,
15. history of seizures in the past 6 months, regardless of seizure type,
16. hyperthyroidism or untreated hypothyroidism,
17. airway instability or pulmonary disease with hypercarbia, or
18. current or past cubital or carpal tunnel syndrome.

4 days