Our results indicate 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 glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and antianhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with standard of care treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699) and 17-M-0060 (NCT03065335). OBJECTIVE: To identify 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 (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes. Secondary Outcome Measures: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e. slow wave sleep EEG activity) are associated with better antidepressant response to 0.5 mg/kg Time Frame: baseline and post-drug To demonstrate enhanced efficacy, as measured by the MADRS, of IV ketamine 0.5 mg/kg in participants with MDD using a psychophysiological technique (i.e. NPU-threat test). Time Frame: baseline and post-drug To identify baseline peripheral measures associated with response to the administration of ketamine 0.5 mg/kg, as potential biomarkers of acute (24 hour) treatment response. Time Frame: baseline and post-drug Results in the past year: 1. Ketamine produces rapid, robust, and fairly sustained antisuicidal ideation effects. Our past work, found that ketamine rapidly reduced suicidal thoughts, with effects lasting up to one week in patients across a range of depressive and non-depressive diagnoses. Suicide is a public health crisis with limited treatment options. We conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation. We found that ketamine rapidly (within 1 day) reduced suicidal ideation significantly. Effect sizes were moderate to large at all time points after dosing. We conclude that ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood. 2. Default Mode Connectivity in Major Depressive Disorder After Ketamine Administration. The symptoms of major depressive disorder (MDD) are rapidly alleviated by administration of a single dose of the glutamatergic modulator ketamine. However, few studies have investigated the potential sustained neural effects of this agent beyond immediate infusion. This study used functional magnetic resonance imaging to examine the effect of a single ketamine infusion on the resting state default mode network (DMN) at 2 and 10 days after a single ketamine infusion in unmedicated subjects with MDD as well as healthy control subjects (HCs). Data were from a double-blind, placebo-controlled crossover study of 58 participants who received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 separate test days spaced 2 weeks apart. Eight minutes of functional magnetic resonance imaging resting state data was acquired at baseline and at about 2 and 10 days after both infusions. In subjects with MDD, connectivity between the insula and the DMN was normalized compared with HCs 2 days postketamine infusion. Group-specific connectivity differences in drug response were observed, most notably in the insula in subjects with MDD and in the thalamus in HCs. In conclusion, connectivity changes in the insula in subjects with MDD suggest that ketamine may normalize the interaction between the DMN and salience networks, supporting the triple network dysfunction model of MDD. 3. Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression. Modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood. This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free MDD subjects and 18 heathy controls who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous saline placebo. Magnetoencephalographic (MEG) recordings were collected prior to the first infusion and six to nine hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Both MDD and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with MDD subjects showing enhanced NMDA connectivity estimates in backward connections, and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our MDD subject group, ketamine efficacy-as measured by improved mood ratings-correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network. In conclusion, these findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that DCM is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo. 4. 7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1H-MRS scans at baseline and at 24h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. No significant between-group differences in 1H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.