Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
Background: Most medications that treat depression take weeks or months to work. Researchers want to develop fast-acting treatments. One dose of ketamine has a rapid antidepressant effect. For most people, this lasts a week or less. Repeated doses of ketamine may help maintain this effect.
Objective: Main Study: To study the effects of ketamine in treating depression. Ketamine Metabolites Substudy: To study how ketamine effects brain chemistry. To study how ketamine effects the brain. This is done by looking at metabolites, which are created when a drug is broken down.
Eligibility: Main Study: People ages 18-65 with major depressive disorder and healthy volunteers Ketamine Metabolites Substudy: Healthy volunteers ages 18-65
Design: Main Study: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks. Phase I (2-7 weeks): * Gradually stop current medications * MRI: Participants lie and perform tasks in a machine that takes pictures of the body. * Mood and thinking tests * Blood and urine tests * Sleep test: Monitors on the skin record brain waves, breathing, heart rate, and movement during sleep. * Transcranial magnetic stimulation: A coil on the scalp gives an electrical current that affects brain activity. * Stress tests: Electrodes on the skin measure reactions to loud noises or electric shocks. Phase I tests are repeated in Phases II and III and in the final visit. Phase II (4-5 weeks): * 4 weekly IV infusions of ketamine or a placebo during an MRI or MEG. For the MEG, a cone over the head records brain activity. Phase III (optional): * 8 infusions of ketamine over 4 weeks Phase IV (optional): * Symptoms monitoring for 4 weeks * Participants will have a final visit. They will be offered standard treatment at NIH for up to 2 months. Ketamine Metabolites Substudy: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 days. Study Procedures: Mood and thinking tests Blood and urine tests 1 infusion of ketamine Spinal tap and spinal catheter: Used to get samples of cerebrospinal fluid (CSF). This is a fluid that moves around and within the brain and spinal cord. Studying CSF will help us learn how ketamine effects brain chemistry
• 18 to 65 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 either protocol 01-M-0254, The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers or protocol 17-M-0181 (Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies).
• Agree to be hospitalized
⁃ Additional Inclusion Criteria: Patients with MDD (Main Study)
• At the initial study enrollment, subjects must have fulfilled DSM-IV or DSM-5 criteria for Major Depression, single episode or recurrent. Subjects must be experiencing a current major depressive episode of at least 2 weeks duration.
• At the initial screening and beginning of Phases II and III, subjects must have a baseline score on the MADRS \>= 20 and YMRS of \< 12.
• Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.
⁃ Ketamine Metabolites Substudy Inclusion Criteria: Healthy Volunteers
• 18 to 65 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 either protocol 01-M-0254 The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers) or 17-M-0181 (Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies).
• Agree to be hospitalized.