Our research suggests that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) resulted in rapid, robust and relatively sustained antidepressant and antisuicidal effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. The current protocol consists of studies designed to address 3 major questions: Study 1: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2: (Biomarkers of rapid response in bipolar depression). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: 1) We found ketamine metabolites that were associated with treatment response. Such metabolites could conceivably be developed to new drugs with a rapid antidepressant onset of action. A US government patent has been filed. 2) Genetics as a predictor of response to ketamine (rapid antidepressant effect) We found that patients with treatment-resistant major depression with the Val/Val BDNF allele had a better rapid antidepressant response to ketamine than patients who were BDNF Met carriers. This is being explored as a biomarker predicting rapid antidepressant response. 3) A family history of alcohol use disorder is associated with rapid antidepressant response to ketamine. Such a finding implicates the possibility of genetics being involved in antidepressant response and could serve as a predictor of response. 4) We found that the metabolites of ketamine have off-site targets, affect other targets than the NMDA receptor suggesting a potential series of new targets to develop antidepressants. 5) In two separate studies (unipolar depression, bipolar depression), we found in brain imaging (Positron Emission Tomography) that certain changes in brain metabolism in areas implicated in depression changed rapidly with ketamine and were associated with treatment response. This is being explored as a biomarker predicting rapid antidepressant response. 6) Certain changes in neuronal proteins were found to occur with ketamine suggesting that these changes might be important in ketamines mechanism of antidepressant action.