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.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$2,688,794
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Lener, Marc S; Niciu, Mark J; Ballard, Elizabeth D et al. (2016) Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biol Psychiatry :
Lally, Níall; An, Li; Banerjee, Dipavo et al. (2016) Reliability of 7T (1) H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation. J Magn Reson Imaging 43:88-98
Ballard, Elizabeth D; Vande Voort, Jennifer L; Bernert, Rebecca A et al. (2016) Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder. J Clin Psychiatry 77:825-31
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Iadarola, Nicolas D; Niciu, Mark J; Richards, Erica M et al. (2015) Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 6:97-114
Ionescu, Dawn F; Luckenbaugh, David A; Niciu, Mark J et al. (2015) A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord 17:438-43
Saligan, Leorey N; Luckenbaugh, David A; Slonena, Elizabeth E et al. (2015) Development of a clinician-administered National Institutes of Health-Brief Fatigue Inventory: A measure of fatigue in the context of depressive disorders. J Psychiatr Res 68:99-105
Machado-Vieira, Rodrigo; Zanetti, Marcus V; Teixeira, Antonio L et al. (2015) Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder. Eur Neuropsychopharmacol 25:468-73
Nugent, Allison C; Martinez, Ashley; D'Alfonso, Alana et al. (2015) The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABAA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy. J Cereb Blood Flow Metab 35:583-91

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