Antidepressant Effects of TS-161 in Treatment-Resistant Depression

Background: Major depressive disorder (MDD) is a common, chronic mental illness. It can take weeks to months for antidepressants to work. Researchers want to test a new drug that might act more rapidly. Objective: To see if TS-161 will improve symptoms of depression in people with MDD. Eligibility: Adults ages 18-65 with MDD without psychotic features. Design: Participants will be screened under a separate protocol. They will have blood tests. They will complete surveys about their symptoms. Participants will have an inpatient visit at NIH. Participation may last 12-16 weeks. During the first phase of the study, participants will be tapered off their psychiatric medicines. For 2 weeks they will have a drug-free period. During Phase II participants will take TS-161 or placebo. They will take TS-161 for 3 weeks and placebo for 3 weeks. In between the 3-week time period, they will have 2-3 weeks where they will be drug free. Participants will also have the following tests during this time: * Interviews * Physical exams * Psychological tests and surveys about their symptoms * Blood draws and urine samples * They may complete tests of mood and thinking * Magnetic resonance imaging (MRI): Participants will lie in a machine that takes pictures of their brain. * Functional MRIs: They will perform tasks displayed on a computer screen inside the MRI scanner * Magnetoencephalography (MEG): Participants will lie down and do tasks of memory, attention, and thinking. A cone lowered on their head will record brain activity. * Electrocardiograms to record the heart s electrical activity. Electrodes will be placed on the skin....