TY - JOUR
T1 - Synaptic mechanisms underlying rapid antidepressant action of ketamine
AU - Kavalali, Ege T
AU - Monteggia, Lisa M
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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 compoundswith effectiveness against other neuropsychiatric disorders.
AB - 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 compoundswith effectiveness against other neuropsychiatric disorders.
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U2 - 10.1176/appi.ajp.2012.12040531
DO - 10.1176/appi.ajp.2012.12040531
M3 - Review article
C2 - 23534055
AN - SCOPUS:84868540518
SN - 0002-953X
VL - 169
SP - 1150
EP - 1156
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 11
ER -