Translational Psychiatry
February 12, 2024
Cheng Jiang, Ralph Dileone, Christopher Pittenger et al.
37 citations
Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions...
Research Square
October 3, 2023
Christopher Pittenger, Cheng Jiang, Ralph Dileone et al.
Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions...
Proceedings for Annual Meeting of The Japanese Pharmacological Society
2022
Ryota Shinohara, Brendan Hare, Rong-Jian Liu et al.
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the prototype for a potential new generation of glutamate-based antidepressants that rapidly relieve symptoms of depression within hours of treatment. Studies in rodents have demonstrated that neuroplasticity in the medial prefrontal cortex (mPFC) is critical for the antidepressant actions of ketamine. However, effector circuits...
Journal of Affective Disorders
2022
L. Averill, C. Averill, R. Gueorguieva et al.
Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we...
The FASEB Journal
May 1, 2021
Santosh Pothula, Rongjian Liu, Min Wu et al.
A single subanesthetic dose of ketamine exerts rapid antidepressant‐like effects via rapid glutamate efflux, activation of mTORC1 signaling, and enhanced synaptic transmission in the medial prefrontal cortex (mPFC); however, the initial cellular trigger for these synaptic and behavioral actions of ketamine still remains unclear. Here, we used electrophysiology, biochemistry, molecular biology...
Neuropsychopharmacology
February 24, 2020
Chadi G. Abdallah, Lynnette A. Averill, Ralitza Gueorguieva et al.
181 citations
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized...
Pharmacology, Biochemistry and Behavior
December 9, 2019
Satoshi Deyama, Ronald S. Duman
181 citations
Clinical and preclinical studies have demonstrated that depression, one of the most common psychiatric illnesses, is associated with reduced levels of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), contributing to neuronal atrophy in the prefrontal cortex (PFC) and hippocampus, and reduced hippocampal adult neurogenesis....
European Journal of Neuroscience
December 6, 2019
Ronald S. Duman, Satoshi Deyama, Manoela V. Fogaça
319 citations
The pathophysiology and treatment of depression have been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to...
Journal of Clinical Investigation
November 19, 2019
Danielle M. Gerhard, Santosh Pothula, Rong-Jian Liu et al.
345 citations
A single sub-anesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates these and its...
Pharmacology, Biochemistry and Behavior
November 13, 2019
Taro Kato, Ronald S. Duman
Conventional antidepressant medications, which act on monoaminergic systems, have significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. Recently, clinical findings demonstrate that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate (NMDA) receptor channel activity, causes rapid (within hours) and long-lasting (7 to 10 days)...
Neurobiology of Disease
November 7, 2019
Sriparna Ghosal, Catharine H. Duman, Rong-Jian Liu et al.
94 citations
Dysfunction of medial prefrontal cortex (mPFC) in association with imbalance of inhibitory and excitatory neurotransmission has been implicated in depression. However, the precise cellular mechanisms underlying this imbalance, particularly for GABAergic transmission in the mPFC, and the link with the rapid acting antidepressant ketamine remains poorly understood. Here we determined the...
Nature Communications
June 3, 2019
Farhan Ali, Danielle M. Gerhard, Katherine Sweasy et al.
201 citations
A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST)...
Journal of Clinical Investigation
April 16, 2019
T. Kato, Santosh Pothula, Rong-Jian Liu et al.
88 citations
Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly...
Neuron
March 1, 2019
John H. Krystal, Chadi G. Abdallah, Gerard Sanacora et al.
443 citations
Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy. The rapid, profound, and sustainable antidepressant effects of ketamine...
Nature Communications
January 15, 2019
Brendan Hare, R. Shinohara, Rong-Jian Liu et al.
Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes,...
American Journal of Psychiatry
January 4, 2019
Satoshi Deyama, Eunyoung Bang, Eric S. Wohleb et al.
100 citations
OBJECTIVE: -methyl-d-aspartate receptor antagonist ketamine produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. Vascular endothelial growth factor (VEGF) has been implicated in the effects of conventional monoamine-based antidepressants, but the role of VEGF in the rapid antidepressant actions of ketamine remains unclear. The authors...
Proceedings of the National Academy of Sciences
December 17, 2018
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu et al.
191 citations
Significance A metabolite of ketamine, (2 R ,6 R )-hydroxynorketamine [(2 R ,6 R )-HNK], produces rapid and sustained antidepressant effects in animal models but without the side effects of ketamine. Notably, (2 R ,6 R )-HNK does not block the NMDA receptor, the primary target of ketamine. Here, we demonstrate that the antidepressant effects of (2 R ,6 R )-HNK require activity dependent release...
F1000Research
May 24, 2018
Ronald S. Duman
203 citations
Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has...
Proceedings for Annual Meeting of The Japanese Pharmacological Society
2018
Satoshi Deyama, Eunyoung Baing, T. Kato et al.
Previous studies have shown that activity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) is required for the antidepressant actions of ketamine. Recently, we have found that neuronal vascular endothelial growth factor (VEGF),signaling in the mPFC also plays a crucial role in the antidepressant actions of this rapid acting agent. However, it...
Chronic Stress
February 1, 2017
Brendan Hare, Sriparna Ghosal, Ronald S. Duman
69 citations
Stress-associated disorders, including depression and anxiety, impact nearly 20% of individuals in the United States. The social, health, and economic burden imposed by stress-associated disorders requires in depth research efforts to identify suitable treatment strategies. Traditional medications (e.g., selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) have significant...
Current Neuropharmacology
March 10, 2016
Eric S. Wohleb, Danielle M. Gerhard, Alex Thomas et al.
148 citations
Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that causes profound social and economic burdens. The impact of MDD is compounded by the limited therapeutic efficacy and delay of weeks to months of currently available medications. These issues highlight the need for more efficacious and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs...
Proceedings of the National Academy of Sciences
June 8, 2015
Manabu Fuchikami, Alexandra M. Thomas, Rongjian Liu et al.
282 citations
Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely...
The International Journal of Neuropsychopharmacology
October 31, 2014
Ashley E. Lepack, Manabu Fuchikami, J. M. Dwyer et al.
369 citations
BACKGROUND: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors...
Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying...
Dialogues in Clinical Neuroscience
March 31, 2014
Ronald S. Duman
248 citations
Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is...