Major depressive disorder (MDD) is one of the most prevalent and debilitating illnesses world wide, affecting 17 percent of the population and causing enormous personal and economic burden. The impact of MDD is underscored by the limitations of currently available medications, including low response rates, treatment resistant patients, and time-lag (weeks to months) for response. These data highlight the major unmet need for more efficacious and faster-acting antidepressant agents. Recent studies demonstrate that a single low dose of ketamine, a glutamate-NMDA receptor antagonist, produces rapid antidepressant actions (2 hr) that last for up to 7 days in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, may represent one of the most significant findings in the field of depression over the past 2 decades. The mechanisms underlying the rapid antidepressant actions of ketamine have not been identified, and the current application addresses this issue. Preliminary studies have found that ketamine rapidly stimulates the mammalian target of rapamycin (mTOR) pathway in rat prefrontal cortex (PFC). The mTOR cascade has been implicated in the regulation of synaptic protein synthesis and activity-dependent enhancement of synaptic strength. Preliminary findings also demonstrate that ketamine rapidly increases spine number and synaptic function of PFC neurons and produces rapid antidepressant behavioral responses in rodent models. Moreover, these actions of ketamine are blocked by rapamycin, demonstrating a requirement for mTOR signaling. Based on these findings, we hypothesize that the rapid antidepressant actions of ketamine result from activation of mTOR signaling, stimulation of synaptic protein synthesis, and increased synapse/spine formation and function in the PFC. This application describes an integrated multidisciplinary approach, including molecular, biochemical, electrophysiological, morphological, and behavioral studies to test this hypothesis.
Aim 1 will characterize the time course and regional localization of ketamine-stimulation of mTOR signaling, synaptic proteins, spines number, function, and behavioral response, as well as confirm the requirement for mTOR using a combination of pharmacological, viral vector, and shRNA approaches. The hypothesis that ketamine can rapidly reverse the deficits in spine number and function resulting from chronic stress exposure will also be tested.
Aim 2 will determine the role of glutamate transmission and neurotrophic factor signaling, which have been implicated in activity-dependent stimulation of mTOR and induction of synaptic strength.
Aim 3 will determine if novel therapeutic targets identified in Aims 1 and 2 produce rapid ketamine-like antidepressant responses or sustain the actions of a single dose of ketamine. Characterization of the signaling pathways that underlie the actions of ketamine will provide novel targets for safer, rapid-acting antidepressants and/or agents that sustain the response to ketamine.

Public Health Relevance

Depression is one of the most prevalent and debilitating illnesses world wide, and the personal and economic burdens of this disorder are underscored by the lack of rapid, safe, and efficacious medications. Recent clinical studies demonstrate that a glutamate-NMDA receptor antagonist, ketamine, produces rapid antidepressant therapeutic responses within hours of treatment and that last for up to 7 days in patients who are resistant to typical antidepressants. Studies are described to identify the cellular signaling mechanisms underlying the rapid antidepressant actions of ketamine, and to utilize this information to test novel therapeutic targets with potential for rapid and efficacious treatment response rates, without the side effects of ketamine, and thereby address a major unmet need for the treatment of depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH093897-01
Application #
8097791
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
1
Fiscal Year
2011
Total Cost
$491,662
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kato, T; Fogaça, M V; Deyama, S et al. (2018) BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol Psychiatry 23:2007-2017
Ghosal, Sriparna; Bang, Eunyoung; Yue, Wenzhu et al. (2018) Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine. Biol Psychiatry 83:29-37
Gerhard, Danielle M; Duman, Ronald S (2018) Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions. Curr Behav Neurosci Rep 5:36-47
Girgenti, Matthew J; Hare, Brendan D; Ghosal, Sriparna et al. (2017) Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD. Curr Psychiatry Rep 19:85
Girgenti, Matthew J; Ghosal, Sriparna; LoPresto, Dora et al. (2017) Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiol Dis 100:1-8
Duman, Ronald S (2017) BDNF, 5-HT, and Anxiety: Identification of a Critical Periadolescent Developmental Period. Am J Psychiatry 174:1137-1139
Banasr, Mounira; Lepack, Ashley; Fee, Corey et al. (2017) Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression. Chronic Stress (Thousand Oaks) 1:
Wohleb, Eric S; Gerhard, Danielle; Thomas, Alex et al. (2017) Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine. Curr Neuropharmacol 15:11-20
Thomas, Alexandra M; Duman, Ronald S (2017) Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms. Neuronal Signal 1:
Chowdhury, G M I; Zhang, J; Thomas, M et al. (2017) Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry 22:120-126

Showing the most recent 10 out of 52 publications