%0 Journal Article %1 kavalali2012synaptic %A Kavalali, E T %A Monteggia, L M %D 2012 %J Am J Psychiatry %K antidepressant eEF2 ketamine signaling %R 10.1176/appi.ajp.2012.12040531 %T Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine %U http://www.ncbi.nlm.nih.gov/pubmed/23034695 %X Recent clinical studies have demonstrated that a single subpsychotomimetic dose of ketamine, an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, produces a rapid antidepressant response in patients with major depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about this unexpected efficacy of ketamine, its widespread use as a fast-acting antidepressant in routine clinical settings is curtailed by its abuse potential as well as possible psychotomimetic effects. However, the ability of ketamine to produce a rapid and long-lasting antidepressant response in patients with depression provides a unique opportunity for investigation of mechanisms that mediate these clinically relevant behavioral effects. From a mechanistic perspective, it is easy to imagine how activation of NMDA receptors may trigger cellular and behavioral responses; it is relatively more difficult, however, to envision how transient blockade of one of the key pathways for neuronal communication produces a persistent beneficial effect. The authors discuss recent work linking ketamine's mechanism of action to homeostatic synaptic plasticity processes activated after suppression of NMDA-mediated glutamatergic neurotransmission. They focus on their recent work demonstrating that ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and desuppression of rapid dendritic protein translation, including BDNF (brain-derived neurotrophic factor), which then contributes to synaptic plasticity mechanisms that mediate long-term effects of the drug. The authors also explore possible molecular strategies to target spontaneous neurotransmitter release selectively to help uncover novel presynaptic avenues for the development of fast-acting antidepressants and possibly psychoactive compounds with effectiveness against other neuropsychiatric disorders.

@article{kavalali2012synaptic, abstract = {Recent clinical studies have demonstrated that a single subpsychotomimetic dose of ketamine, an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, produces a rapid antidepressant response in patients with major depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about this unexpected efficacy of ketamine, its widespread use as a fast-acting antidepressant in routine clinical settings is curtailed by its abuse potential as well as possible psychotomimetic effects. However, the ability of ketamine to produce a rapid and long-lasting antidepressant response in patients with depression provides a unique opportunity for investigation of mechanisms that mediate these clinically relevant behavioral effects. From a mechanistic perspective, it is easy to imagine how activation of NMDA receptors may trigger cellular and behavioral responses; it is relatively more difficult, however, to envision how transient blockade of one of the key pathways for neuronal communication produces a persistent beneficial effect. The authors discuss recent work linking ketamine's mechanism of action to homeostatic synaptic plasticity processes activated after suppression of NMDA-mediated glutamatergic neurotransmission. They focus on their recent work demonstrating that ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and desuppression of rapid dendritic protein translation, including BDNF (brain-derived neurotrophic factor), which then contributes to synaptic plasticity mechanisms that mediate long-term effects of the drug. The authors also explore possible molecular strategies to target spontaneous neurotransmitter release selectively to help uncover novel presynaptic avenues for the development of fast-acting antidepressants and possibly psychoactive compounds with effectiveness against other neuropsychiatric disorders.}, added-at = {2013-01-09T14:45:48.000+0100}, author = {Kavalali, E T and Monteggia, L M}, biburl = {https://www.bibsonomy.org/bibtex/271da9dfe20d50d8d83f522bb4aec0a59/kilianjay}, description = {Synaptic Mechanisms Underlying Rapid Antidep... [Am J Psychiatry. 2012] - PubMed - NCBI}, doi = {10.1176/appi.ajp.2012.12040531}, interhash = {88e35a069103074b1b9455bee280bc9e}, intrahash = {71da9dfe20d50d8d83f522bb4aec0a59}, journal = {Am J Psychiatry}, keywords = {antidepressant eEF2 ketamine signaling}, month = oct, pmid = {23034695}, timestamp = {2013-01-15T16:44:04.000+0100}, title = {Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23034695}, year = 2012 }