The Mechanism of Action Underlying Ketamine's Antidepressant Effects: An Investigation of 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.
⁃ Phases I-II
• 18 to 70 years of age.
• Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
• 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.
• 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).
• Subjects must have an initial score on the MADRS greater than or equal to 22 and a YMRS score of \<12 within one week of study entry and upon entry into Phase II.
• Lack of response to two adequate antidepressant trials, with \[at least\] one in the current major depressive episode, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT \[or TMS\] would count as an adequate antidepressant trial.
• Current major depressive episode lasting at least four weeks
• Agree to be hospitalized
⁃ Open-Label Ketamine Treatment
• Participants must have met all inclusion criteria for and completed Study Phase II
• Individuals who are able to get pregnant must be willing to remain sexually abstinent or use at least one form of effective birth control during participation in Phase III.