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Fast acting antidepressant

Vivian B Neis, Luis E B Bettio, Morgana Moretti, Priscila B Rosa, Camille M Ribeiro, Andiara E Freitas, Filipe M Gonçalves, Rodrigo B Leal, Ana Lúcia S Rodrigues
Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants...
October 12, 2016: Pharmacology, Biochemistry, and Behavior
N Z Kara, G Agam, G W Anderson, N Zitron, H Einat
The acute antidepressant effects of ketamine provide hope for the development of a fast acting approach to treat depression but the consequences of chronic treatment with ketamine are still unclear. One theory regarding the acute effect is that ketamine acts through activation of mTOR but chronic activation of mTOR may lead to reduced autophagy and reduced autophagy could have negative consequences on neuronal plasticity and survival and on affect. To study the interaction between chronic ketamine administration, autophagy and depression the present study tested the effects of 3 weeks daily administration of 5 or 10mg/kg ketamine in both female and male ICR mice on behavior in the open field and the forced swim test and on frontal cortex levels of beclin-1 and p62, two proteins that serve as markers of autophagy...
September 26, 2016: Behavioural Brain Research
Ashley E Lepack, Eunyoung Bang, Boyoung Lee, Jason M Dwyer, Ronald S Duman
Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner...
December 2016: Neuropharmacology
Ke Zhang, Vitor Nagai Yamaki, Zhisheng Wei, Yu Zheng, Xiang Cai
Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants...
January 1, 2017: Behavioural Brain Research
Roberto Cadeddu, Dragana Jadzic, Ezio Carboni
Since the therapeutic treatment of depression is far from being satisfactory, new therapeutic strategies ought to be pursued. In addition, further investigation on brain areas involved in the action mechanism of antidepressants can shed light on the aetiology of depression. We have previously reported that typical and atypical antidepressants strongly stimulate catecholamine transmission in the bed nucleus of stria terminalis (BNST). In this study, we have built on that work to examine the effect of ketamine, an unusual antidepressant that can produce a fast-acting and long-lasting antidepressant effect after administration of a single sub-anaesthetic dose...
October 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Priscila B Rosa, Vivian B Neis, Camille M Ribeiro, Morgana Moretti, Ana Lúcia S Rodrigues
BACKGROUND: It has been suggested that dysregulation of γ-aminobutyric acid (GABA)-mediated neurotransmission is involved in the etiology of major depressive disorder and in the action of the fast-acting antidepressant ketamine. Considering that recent evidence has suggested that ascorbic acid may exert an antidepressant-like effect through mechanisms similar to ketamine, this study evaluated the involvement of GABAA and GABAB receptors in the antidepressant-like effect of ascorbic acid, comparing the results with those obtained with ketamine...
October 2016: Pharmacological Reports: PR
E M Meylan, L Breuillaud, T Seredenina, P J Magistretti, O Halfon, R Luthi-Carter, J-R Cardinaux
Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1(-/-) mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1(-/-) mice...
2016: Translational Psychiatry
Luca Muzio, Valentina Brambilla, Lorenza Calcaterra, Patrizia D'Adamo, Gianvito Martino, Francesco Benedetti
The search for biomarkers of antidepressant effects focused on pathways regulating synaptic plasticity, and on activated inflammatory markers. Repeated Sleep Deprivation (SD) provides a model treatment to reverse-translate antidepressant effects from in vivo clinical psychiatry to model organisms. We studied the effects of repeated SD alone (ASD) or combined with exercise on a slow spinning wheel (SSW), in 116 C57BL/6J male mice divided in three groups (ASD, SSW, untreated). Forced Swimming Test (FST) was used to detect antidepressant-like effects...
September 15, 2016: Behavioural Brain Research
Paul Glue, Colleen Loo, Anthony Rodgers, Verònica Gálvez, Andrew A Somogyi, Philip B Mitchell
No abstract text is available yet for this article.
May 27, 2016: World Journal of Biological Psychiatry
Madhavi Pusalkar, Shreya Ghosh, Minal Jaggar, Basma Fatima Anwar Husain, Sanjeev Galande, Vidita A Vaidya
BACKGROUND: Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. METHODS: We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis...
May 17, 2016: International Journal of Neuropsychopharmacology
Joanna Ficek, Magdalena Zygmunt, Marcin Piechota, Dzesika Hoinkis, Jan Rodriguez Parkitna, Ryszard Przewlocki, Michal Korostynski
BACKGROUND: The NMDA receptor antagonist ketamine was found to act as a fast-acting antidepressant. The effects of single treatment were reported to persist for days to weeks, even in otherwise treatment-refractory cases. Identification of the mechanisms underlying ketamine's antidepressant action may permit development of novel drugs, with similar clinical properties but lacking psychotomimetic, sedative and other side effects. METHODS: We applied whole-genome microarray profiling to analyze detailed time-course (1, 2, 4 and 8 h) of transcriptome alterations in the striatum and hippocampus following acute administration of ketamine, memantine and phencyclidine in C57BL/6 J mice...
2016: BMC Genomics
Victoria Phoumthipphavong, Florent Barthas, Samantha Hassett, Alex C Kwan
A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice...
March 2016: ENeuro
Vivian Binder Neis, Morgana Moretti, Luis Eduardo B Bettio, Camille M Ribeiro, Priscila Batista Rosa, Filipe Marques Gonçalves, Mark William Lopes, Rodrigo Bainy Leal, Ana Lúcia S Rodrigues
The activation of AMPA receptors and mTOR signaling has been reported as mechanisms underlying the antidepressant effects of fast-acting agents, specially the NMDA receptor antagonist ketamine. In the present study, oral administration of agmatine (0.1mg/kg), a neuromodulator that has been reported to modulate NMDA receptors, caused a significant reduction in the immobility time of mice submitted to the tail suspension test (TST), an effect prevented by the administration of DNQX (AMPA receptor antagonist, 2...
June 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Ambalika Sarkar, Mohamed Kabbaj
BACKGROUND: The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. METHODS: We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus...
September 15, 2016: Biological Psychiatry
Gislaine Z Réus, Helena M Abelaira, Talita Tuon, Stephanie E Titus, Zuleide M Ignácio, Ana Lúcia S Rodrigues, João Quevedo
Major depressive disorder (MDD) affects approximately 121 million individuals globally and poses a significant burden to the healthcare system. Around 50-60% of patients with MDD respond adequately to existing treatments that are primarily based on a monoaminergic system. However, the neurobiology of MDD has not been fully elucidated; therefore, it is possible that other biochemical alterations are involved. The glutamatergic system and its associated receptors have been implicated in the pathophysiology of MDD...
2016: Advances in Protein Chemistry and Structural Biology
Amber M Leaver, Randall Espinoza, Tara Pirnia, Shantanu H Joshi, Roger P Woods, Katherine L Narr
INTRODUCTION: One of the most effective interventions for intractable major depressive episodes is electroconvulsive therapy (ECT). Because ECT is also relatively fast-acting, longitudinal study of its neurobiological effects offers critical insight into the mechanisms underlying depression and antidepressant response. Here we assessed modulation of intrinsic brain activity in corticolimbic networks associated with ECT and clinical response. METHODS: We measured resting-state functional connectivity (RSFC) in patients with treatment-resistant depression (n=30), using functional magnetic resonance imaging (fMRI) acquired before and after completing a treatment series with right-unilateral ECT...
January 2016: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Cristiano Chiamulera, Federica Armani, Anna Mutti, Liana Fattore
Methoxetamine (MXE) is a chemical analogue of ketamine. Originally proposed as a ketamine-like fast-acting antidepressant, owing to similar N-methyl-D-aspartate blocker properties, it is now scheduled for reports of hallucinations and psychosis similar to ketamine and lysergic acid. As little is known about the addictive properties of MXE, the aim of this study was to investigate the similarity between discriminative stimuli of MXE and ketamine, as well as to provide data and protocols that could be used in the future for the characterization of novel ketamine-like drugs...
April 2016: Behavioural Pharmacology
Elias Wolf, Marion Kuhn, Claus Norman, Florian Mainberger, Jonathan G Maier, Sarah Maywald, Aliza Bredl, Stefan Klöppel, Knut Biber, Dietrich van Calker, Dieter Riemann, Annette Sterr, Christoph Nissen
Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i...
November 30, 2015: Sleep Medicine Reviews
Zhen-Yong Gao, Ping Yang, Qing-Jun Huang, Hai-Yun Xu
Clinical studies have demonstrated that a single dose of ketamine produces complete remission within 24h in some depression patients. The ability of ketamine to produce fast-acting antidepressant-like effects in animal models depends on rapid synthesis of brain-derived neurotrophic factor (BDNF). Here we examined effects of a single dose dizocilpine, a non-competitive NMDA receptor antagonist, on the behavioral and neurobiological changes in rats treated with a single high dose reserpine, which is a monoamine re-uptake blocker and depletes monoamines in the brain with the outcome of depression-like symptoms in animals...
February 12, 2016: Neuroscience Letters
Karen Schmitt, Edith Holsboer-Trachsler, Anne Eckert
The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD)...
2016: Annals of Medicine
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