Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine

• Published in: The American journal of psychiatry 2012-11, Vol.169 (11), p.1150-1156
• Main Authors: Kavalali, Ege T., Monteggia, Lisa M.
• Format: Article
• Language: English
• Subjects: Animals; Antidepressants; Antidepressive Agents - pharmacology; Biological and medical sciences; Brain - drug effects; Disease Models, Animal; Humans; Ketamine - pharmacology; Medical sciences; Mental depression; Mice; Neurobiology; Neuronal Plasticity - drug effects; Neuropharmacology; Neurotransmitter Agents - metabolism; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychoanalysis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Signal Transduction - drug effects; Synapses - drug effects; Synaptic Transmission - drug effects; Synaptic Vesicles - drug effects
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.2012.12040531

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.