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R. Duman

Ketamine: A Paradigm Shift for Depression Research and Treatment

March 6, 2019 / Depressive Disorders, Papers, Psychology, Publications / By / , , , ,

Abstract

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.
Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778., 10.1016/j.neuron.2019.02.005
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Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

May 24, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By /

Abstract

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 invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.
Duman, R. S. (2018). Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Research, 7. 10.12688/f1000research.14344.1
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Convergent Mechanisms Underlying Rapid Antidepressant Action

March 1, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018). Convergent mechanisms underlying rapid antidepressant action. CNS drugs, 1-31. 10.1007/s40263-018-0492-x
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Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

August 26, 2017 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

PURPOSE OF REVIEW:
Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.
RECENT FINDINGS:
Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.
Krystal, J. H., Abdallah, C. G., Averill, L. A., Kelmendi, B., Harpaz-Rotem, I., Sanacora, G., … & Duman, R. S. (2017). Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Current Psychiatry Reports, 19(10), 74. 10.1007/s11920-017-0829-z
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Ketamine accelerates fear extinction via mTORC1 signaling

December 30, 2016 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24 h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8 days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.

Girgenti, M. J., Ghosal, S., LoPresto, D., Taylor, J. R., & Duman, R. S. (2017). Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology of Disease, 100, 1-8. 10.1016/j.nbd.2016.12.026
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Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics

October 17, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

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 the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.

Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015). Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics. Medicine, 66. https://dx.doi.org/10.1146/annurev-med-053013-062946

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