INCLUSION CRITERIA:  Participants may be eligible for this study if they:  Are able to understand the study and can provide your own consent. Are willing to undergo all study procedures and are available for the duration of the study. Are aged 18 to 65. Have major depressive disorder. Have a current episode of depression lasting at least 4 weeks. Ability to take oral medication. Have not responded to at least one antidepressant. For females of reproductive potential: use of contraception while in the study and for an additional 4 weeks after stopping the study drug. For males of reproductive potential: use of condoms or other types of birth control with partner while in the study and for an additional 3 months after stopping the study drug. Agree to be hospitalized at the NIH Clinical Center. Abstain from alcohol and drug use while in the study.  EXCLUSION CRITERIA:  Participants may not be eligible for this study if they:  Are taking any medications that might make it unsafe for you to receive TS-161 or might interfere with our study results. Have been treated with a reversible monoamine oxidase inhibitor (such as phenelzine (Nardil) and tranylcypromine (Parnate)), clozapine, or electroconvulsive therapy (ECT) less than 4 weeks before Phase II. Have been treated with fluoxetine, aripiprazole, or brexpiprazole less than 5 weeks before Phase II. Have ever undergone deep brain stimulation. Have taken ketamine or esketamine for the treatment of depression but did not respond. Are unwilling to stop undergoing one-on-one psychotherapy for the duration of the study. Are pregnant or plan to become pregnant in the next 12 to 16 weeks while in the study, or are breast-feeding. Have schizophrenia or any other psychotic disorder. Had significant drug or alcohol dependence or abuse in the past 3 months (except for nicotine or caffeine), or are currently using illicit substances. Have been diagnosed with borderline or antisocial personality disorder. Had a head injury that caused a loss of consciousness for more than 5 minutes (for the brain imaging). Have a medical illness that might make your participation unsafe, such as heart (including coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), liver, respiratory, blood, immune, or kidney disease or a seizure disorder, based on our evaluation. Have abnormal results on blood and urine tests we will do. Have significant suicidal or homicidal thoughts. Have a positive HIV test. For brain imaging: Have metal in your body which would make having an MRI scan unsafe, such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves, cochlear implants or shrapnel fragments, or if you were a welder or metal worker, since you may have small metal fragments in the eye. Weigh over 245 lbs and cannot fit into the MRI scanner. Have a positive, or suspected positive, COVID-19 test. Are an NIMH staff member or an immediate family member of an NIMH staff member.