A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists.
Ronald S. Duman,Nanxin Li +1 more
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TLDR
Ketamine causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins, which rapidly reverse the atrophy of PFC neurons caused by chronic stress.Abstract:
Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.read more
Citations
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The organization of the stress system and its dysregulation in depressive illness
TL;DR: It is postulate that depression, like autoimmunity, represents a dysregulated adaptive response: a stress response that has gone awry and the cardinal manifestation of the normal stress response is anxiety.
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Integrating neuroimmune systems in the neurobiology of depression
TL;DR: Interventions targeting immune-related cellular and molecular pathways may benefit subsets of MDD patients with immune dysregulation and ongoing studies examining neuroimmune mechanisms that influence neuronal activity as well as synaptic plasticity are discussed.
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The role of 5-HT receptors in depression
TL;DR: The role of serotonin in three distinct hypotheses that have been proposed over the last several decades to explain the pathophysiology of depression are revisited: the monoamine, neurotrophic, and neurogenic hypotheses.
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Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression
TL;DR: A model of serotonin-PFC circuitry that integrates evidence from mouse genetic models of anxiety and depression involving knockout, suppression, over-expression, or mutation of genes of the serotonin system including 5-HT1A receptors is presented.
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Ketamine for treatment-resistant unipolar depression: current evidence.
Sanjay J. Mathew,Sanjay J. Mathew,Sanjay J. Mathew,Asim A Shah,Kyle A.B. Lapidus,Crystal T. Clark,Crystal T. Clark,Noor Jarun,Britta Ostermeyer,James W. Murrough +9 more
TL;DR: The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression.
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