Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression

Background: Most drugs that treat mood disorders take a long time to work. Ketamine works within hours. A dose can last for a week or more. Certain receptors in the brain might help ketamine work. A drug that blocks these receptors might affect how it works. Objective: To see if the antidepressant response of ketamine is linked to AMPA receptors. Eligibility: Adults ages 18-70 with major depression disorder without psychotic features Design: Participants will be screened under protocol 01-M-0254. They will have blood tests and a physical exam. Participants will stay at the NIH Clinical Center for 5 weeks. Phase 1 lasts 4 weeks. For 2 weeks, participants will taper off their psychiatric medicine. Then they will have the following tests: * Blood draws * Psychological tests * MRI: Participants will lie in a machine that takes pictures of their brain. * MEG: Participants will lie down and do tasks. A cone lowered on their head will record brain activity. * Optional sleep tests: Electrodes on the scalp and body and belts around the body will monitor participants while they sleep. * Optional TMS: Participants will do tasks while a wire coil is held on their scalp. An electrical current will pass through the coil that affects brain activity. For phase 2, on day 0 participants will take the study drug or a placebo orally. While having a MEG, they will get ketamine infused into a vein in one arm while blood is drawn from a vein in the other arm. On day 1, participants will again take the study drug or a placebo orally. On days 3-7, they will repeat many of the phase 1 tests. Days 8 and 9 are optional and include an open label ketamine treatment and many of the phase 1 tests.

* INCLUSION CRITERIA: Phases I-II 1. 18 to 70 years of age. 2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document. 3. All subjects must have undergone a screening assessment under protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers". 4. Subjects must fulfill DSM-IV or -5criteria for Major Depression (Major Depressive Disorder) without psychotic features, based on clinical assessment and informed by a structured diagnostic interview (SCID-P). 5. Subjects must have an initial score on the MADRS greater than or equal to 22 and a YMRS score of \ 119 kg 11. Treatment with any concomitant psychiatric medication prior to entering Phase II. \[Medications must be tapered during Phase I.\] 12. Treatment with any non-psychiatric medication/s. 13. Any use of opioid medication in the past 3 months 14. Treatment with a reversible monoamine oxidase inhibitor (MAOI) prior to entering Phase II. \[Medications must be tapered during Phase I.\] 15. Treatment with fluoxetine or aripiprazole at the time of screening. 16. Unwilling to stop undergoing structured, individualized psychotherapy. (Such therapy, including CBT, will not be permitted during Phases I and II of the study.) 17. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clip). 18. Participants who are uncomfortable in small closed spaces (have claustrophobia). 19. Are unable to lie comfortably supine for up to 90 minutes and would feel uncomfortable in the MRI and MEG machines. 20. Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk. 21. Subjects who have a history of aggressive behavior towards others 22. A current NIMH employee/staff or their immediate family member Open-Label Ketamine Treatment 1. Intolerable or serious adverse reaction to ketamine during Phase II 2. Participants with a positive urine for an illicit substance no more than 24 hours prior to ketamine treatment. 3. Pregnant or nursing individuals or those who plan to become pregnant.