This Report involves work collected under protocol 04-M-0222 (NCT00088699). Our research suggests that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. 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. Study: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To determine the neural correlates 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 (ketamine); onset occurred within 2 hours post-infusion 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 these data/outcome measures: 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. Lithium and valproate, two mood stabilizers, do not correlate with ketamine's antidepressant efficacy in treatment-resistant bipolar depression. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. In 36 patients with treatment-resistant bipolar depression maintained on therapeutic doses of lithium or valproate, we did not find that lithium potentiates ketamine's antidepressant efficacy in treatment-resistant bipolar depression. 2. Ketamine produces rapid anti-anhedonic effects. We found that ketamine rapidly improves anhedonia (lack of pleasure) in patients with treatment-resistant depression (major depressive disorder and bipolar disorder). 3. We identified the neural correlates of change in anhedonia in patients with major depressive disorder and bipolar disorder following treatment with ketamine. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC. 4. Ketamine produces rapid antisuicidal effects within hours and lasts at least one week following a single infusion. 5. We identified the neural correlates of change in suicidal thoughts in patients with major depressive disorder and bipolar disorder following treatment with ketamine. Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex.