Science
August 19, 2010
Nanxin Li, Boyoung Lee, Rongjian Liu et al.
2,875 citations
Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
Science
October 4, 2012
Ronald S. Duman, George K. Aghajanian
1,613 citations
Depression involves shrinkage of brain regions that regulate mood and cognition, such as the prefrontal cortex and hippocampus, along with reduced neuronal synapses in those areas. Typical antidepressants can reverse some of these deficits but work slowly and have limited effectiveness. Ketamine, a drug that blocks N-methyl-D-aspartate receptors, rapidly (within hours) improves symptoms in patients who do not respond to standard antidepressants. In basic studies, ketamine quickly promotes the formation of new synapses and reverses the synaptic damage caused by chronic stress. These findings suggest that maintaining healthy mood circuit connections is central to depression and its treatment, forming the basis of a synaptogenic hypothesis.
Journal of Neuroscience
April 15, 1997
Vidita A Vaidya, Gerard J. Marek, George K. Aghajanian et al.
482 citations
A hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, differentially regulated BDNF mRNA levels in rat brain. In the hippocampus, it decreased BDNF mRNA in the dentate gyrus granule cell layer without affecting CA subfields. In neocortical areas (but not piriform cortex), it dramatically increased BDNF mRNA. These effects were blocked by a selective 5-HT2A, but not 5-HT2C, receptor antagonist. Stress-induced downregulation of BDNF mRNA in hippocampus was blocked by pretreatment with ketanserin, a 5-HT2A/2C antagonist, suggesting 5-HT2A receptors mediate that effect. The findings suggest hallucinogenic 5-HT2A agonists may alter synaptic strength in hippocampus and neocortex, potentially mediating behavioral effects.
Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine, a glutamate-based antidepressant, can rapidly alleviate depression within hours of treatment. Replicated evidence shows its rapid and potent effects in treatment-resistant depression. Preclinical and biomarker studies have begun to explain the mechanism behind these rapid effects, offering new insights into depression's biology and identifying potential treatment targets. This article discusses ketamine's efficacy, safety, and tolerability, summarizes depression's neurobiology, reviews the mechanisms of ketamine's rapid antidepressant effects, and considers prospects for next-generation rapid-acting antidepressants.
Philosophical Transactions of the Royal Society B Biological Sciences
July 23, 2012
Ronald S. Duman, Nanxin Li
361 citations
Stress and antidepressant treatments have opposing effects on neurotrophic factors like brain-derived neurotrophic factor in brain regions such as the hippocampus and prefrontal cortex (PFC). Stress reduces these factors, leading to decreased neurogenesis, dendrite length, and spine density, which may contribute to the reduced brain volume seen in depressed patients. Antidepressant treatments can block or reverse this atrophy. A novel rapid-acting antidepressant, ketamine, an NMDA receptor antagonist, rapidly induces synaptogenesis and spine formation in the PFC by stimulating the mammalian target of the rapamycin signaling pathway and increasing synaptic protein synthesis. These effects reverse chronic stress-induced PFC neuron atrophy and correspond to rapid behavioral actions in depression models, identifying new cellular targets for rapid antidepressant actions without ketamine's side effects.
European Journal of Neuroscience
December 6, 2019
Ronald S. Duman, Satoshi Deyama, Manoela V. Fogaça
319 citations
Stress and depression cause neuron atrophy and reduced synaptic connectivity in the hippocampus and prefrontal cortex, contributing to depressive behaviors. Antidepressant treatment can reverse these deficits. Brain-derived neurotrophic factor (BDNF) is key: stress decreases BDNF expression in these regions, while antidepressants up-regulate it. Rapid-acting antidepressants like ketamine produce fast synaptic and behavioral effects dependent on activity-dependent BDNF release, unlike typical monoaminergic agents that require chronic administration for slow BDNF induction. Other rapid-acting agents also require BDNF release, indicating a convergent downstream mechanism. Ketamine's actions also depend on vascular endothelial growth factor (VEGF) and its interplay with BDNF.
Proceedings of the National Academy of Sciences
June 8, 2015
Manabu Fuchikami, Alexandra M. Thomas, Rongjian Liu et al.
282 citations
Ketamine's rapid and sustained antidepressant and anxiolytic effects depend on neuronal activity in the infralimbic prefrontal cortex (IL-PFC). Inactivating the IL-PFC in rodents completely blocked the behavioral effects of systemic ketamine, while direct microinfusion of ketamine into the IL-PFC reproduced those effects. Optogenetic stimulation of the IL-PFC alone also produced rapid, long-lasting antidepressant and anxiolytic effects, which were linked to increased number and function of spine synapses in layer V pyramidal neurons. The findings demonstrate that activating the IL-PFC is sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to those from systemic ketamine.
Dialogues in Clinical Neuroscience
March 31, 2014
Ronald S. Duman
248 citations
Stress and depression cause loss of synaptic connections in brain regions like the prefrontal cortex and hippocampus, partly through decreased brain-derived neurotrophic factor (BDNF). Typical antidepressants struggle to reverse these structural changes. Ketamine, an NMDA receptor antagonist, rapidly increases spine synapses in the prefrontal cortex and reverses chronic stress deficits in animal models, likely by disinhibiting glutamate transmission, boosting BDNF release, and activating synapse-forming pathways. Scopolamine, a muscarinic receptor antagonist, similarly increases glutamate transmission and synapse formation. These findings have led to testing of additional agents that influence glutamate transmission, showing rapid antidepressant effects in rodent models and clinical trials.
Depression and Anxiety
March 10, 2014
Ronald S. Duman
213 citations
Stress and depression cause atrophy and loss of neurons in brain regions involved in emotion and cognition, which may contribute to depressive symptoms. Standard antidepressants, which target monoamine neurotransmitters, have limited effectiveness and require long-term use, and they only weakly counteract these stress-induced structural changes. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in difficult-to-treat patients. Preclinical studies show ketamine rapidly increases synaptic connections in the prefrontal cortex by boosting glutamate signaling and activating pathways that control synaptic protein synthesis, and it reverses synaptic deficits caused by chronic stress in rodents. These findings reveal new targets for rapid-acting antidepressants with fewer side effects and improve understanding of stress, depression, and treatment response.
F1000Research
May 24, 2018
Ronald S. Duman
203 citations
A single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, produces a rapid antidepressant response within hours that lasts about a week, even in treatment-resistant patients, and also treats suicidal ideation. Efforts are developing ketamine-like drugs with fewer side effects, including ketamine metabolites, stereoisomers, NMDA allosteric modulators, and mGluR2/3 autoreceptor blockers. Other targets enhancing glutamate neurotransmission or synaptic function, such as scopolamine and mTORC1 signaling activators, are being investigated. This discovery heralds a new era for developing rapid and efficacious antidepressant medications.
Proceedings of the National Academy of Sciences
December 17, 2018
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu et al.
191 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
The International Journal of Neuropsychopharmacology
November 24, 2011
Jason M. Dwyer, Ashley E. Lepack, Ronald S. Duman
169 citations
A single dose of LY 341495, an mGluR₂/₃ antagonist, rapidly activates the mTOR pathway and increases synaptic proteins in the prefrontal cortex, similar to the fast-acting antidepressant ketamine. Within one hour, LY 341495 activates mTOR, p70S6K, and 4E-BP1, and 24 hours later elevates levels of PSD-95, GluR1, and Synapsin I. The antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor rapamycin, indicating that these actions are mediated by mTOR activation. This suggests mGluR₂/₃ antagonists could produce rapid antidepressant effects in depressed patients.
Current Neuropharmacology
March 10, 2016
Eric S. Wohleb, Danielle M. Gerhard, Alex Thomas et al.
148 citations
Major depressive disorder (MDD) is a common neuropsychiatric disease with limited treatment options that take weeks to work. Recent breakthroughs show that drugs like ketamine and scopolamine produce rapid and long-lasting antidepressant effects in MDD patients. Preclinical work in rodents indicates these effects arise from increased extracellular glutamate, elevated BDNF, activation of the mTORC1 cascade, and increased spine synapses in the prefrontal cortex (PFC). Both drugs work through converging molecular and cellular mechanisms in the PFC, antagonizing inhibitory interneurons to disinhibit pyramidal neurons, boosting glutamate. Specific NMDA and muscarinic acetylcholine receptor subtypes on GABAergic interneurons are promising targets for new rapid-acting antidepressants.
American Journal of Psychiatry
January 4, 2019
Satoshi Deyama, Eunyoung Bang, Eric S. Wohleb et al.
100 citations
The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
Neurobiology of Disease
November 7, 2019
Sriparna Ghosal, Catharine H. Duman, Rong-Jian Liu et al.
94 citations
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
Journal of Clinical Investigation
April 16, 2019
T. Kato, Santosh Pothula, Rong-Jian Liu et al.
88 citations
A single dose of NV-5138, a small molecule that modulates sestrin and crosses the blood-brain barrier, produced rapid and long-lasting antidepressant effects and quickly reversed anhedonia caused by chronic stress in mice. These effects required BDNF release in the medial prefrontal cortex, as blocking BDNF with an antibody or using a BDNF polymorphism that prevents activity-dependent release eliminated the behavioral responses. NV-5138 also rapidly increased synapse number and function in the medial prefrontal cortex and reversed synaptic deficits from chronic stress. The findings indicate that pharmacologically modulating sestrin activates mTORC1 signaling and BDNF release, offering a new approach for rapid-acting antidepressants.
Journal of Molecular Psychiatry
September 17, 2013
Jason M. Dwyer, Ashley E. Lepack, Ronald S. Duman
81 citations
A single injection of the experimental compound LY341495, which blocks mGluR2/3 receptors, rapidly and lastingly reversed anhedonia—a core symptom of depression—in rats subjected to chronic unpredictable stress. The effect appeared within one to two days and persisted for at least ten days, a timeline comparable to the rapid antidepressant action of ketamine but without ketamine's side effects and abuse potential. Typical antidepressants require weeks to produce a response. The findings suggest that mGluR2/3 antagonists may offer a safer alternative for fast-acting depression treatment.
Chronic Stress
February 1, 2017
Brendan Hare, Sriparna Ghosal, Ronald S. Duman
69 citations
Stress-related disorders like depression and anxiety affect nearly 20% of people in the United States. Traditional antidepressants such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors have drawbacks, including a delayed therapeutic response and low efficacy. Ketamine works rapidly and helps treatment-resistant patients, but its use is limited by temporary dissociative and psychotomimetic side effects and potential for abuse. Rodent stress models produce behavioral, molecular, and cellular changes in brain regions like the prefrontal cortex and hippocampus that resemble those in depression. Rapid-acting antidepressants like ketamine can reverse these stress-induced changes. This review examines how these agents counteract stress and explores their molecular, cellular, and circuit-level targets.
Translational Psychiatry
February 12, 2024
Cheng Jiang, Ralph Dileone, Christopher Pittenger et al.
37 citations
A single dose of ketamine produces antidepressant-like effects in rats only when the brain's own opioid system is active in the medial prefrontal cortex (mPFC). Blocking opioid receptors with naltrexone—either throughout the body or directly in the mPFC—eliminates ketamine's behavioral effects. Ketamine rapidly increases levels of the opioid β-endorphin and expression of the μ-opioid receptor gene in the mPFC, and boosts production of β-endorphin's precursor in the hypothalamus. Neutralizing β-endorphin in the mPFC with a specific antibody also abolishes ketamine's behavioral and molecular effects, demonstrating that β-endorphin and opioid receptor activation in the mPFC are necessary for ketamine's antidepressant-like actions.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
January 1, 2022
Ryota Shinohara, Brendan Hare, Rong-Jian Liu et al.
Ketamine, an NMDA receptor antagonist, rapidly relieves symptoms of depression within hours. While neuroplasticity in the medial prefrontal cortex (mPFC) is known to be critical for these effects, the downstream brain circuits involved were unclear. Using optogenetic and chemogenetic techniques in rodent models, researchers identified two distinct pathways. Activation of mPFC projections to the basolateral amygdala (BLA) and then to the ventral hippocampus mediated ketamine's effects on passive coping behavior, but not on anxiety or reward-seeking. In contrast, mPFC projections to the bed nucleus of stria terminalis (BNST) were necessary and sufficient for effects on anxiety-like and reward-seeking behaviors, but not passive coping. This suggests separate downstream circuits produce different antidepressant-like behavioral responses.
The FASEB Journal
May 1, 2021
Santosh Pothula, Rongjian Liu, Min Wu et al.
Ketamine's rapid antidepressant effects depend on GluN2B-containing NMDA receptors on somatostatin-expressing (Sst) interneurons in the medial prefrontal cortex (mPFC). In mice, a single subanesthetic dose of ketamine reduced NMDA-induced burst firing of Sst-interneurons, decreased inhibitory transmission, and increased excitatory transmission in layer V pyramidal neurons, reversing behavioral deficits caused by chronic unpredictable stress. These effects were absent in mice lacking GluN2B from Sst-interneurons. The findings identify Sst-interneurons as the initial cellular trigger for ketamine's synaptic and behavioral actions, supporting the disinhibition hypothesis whereby ketamine disinhibits pyramidal neurons via GluN2B-NMDARs on Sst-interneurons, activating mTOR signaling and enhancing synaptic function.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
January 1, 2018
Satoshi Deyama, Eunyoung Baing, T. Kato et al.
Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the medial prefrontal cortex (mPFC) work together to produce antidepressant effects. In cultured cortical neurons, BDNF stimulates VEGF release and VEGF stimulates BDNF release. BDNF increases dendritic complexity, but this effect is blocked by inhibiting the VEGF receptor Flk-1; similarly, VEGF's effect on dendrites is blocked by inhibiting the BDNF receptor TrkB. A single infusion of either BDNF or VEGF into the mPFC of mice produces antidepressant effects lasting at least 5 days in three behavioral tests. These effects are blocked by neutralizing the other factor, indicating that mutual signaling between BDNF and VEGF is required for rapid and sustained antidepressant responses.