Signaling pathways underlying the rapid antidepressant actions of ketamine

• Published in: Neuropharmacology 2012-01, Vol.62 (1), p.35-41
• Main Authors: Duman, Ronald S., Li, Nanxin, Liu, Rong-Jian, Duric, Vanja, Aghajanian, George
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Depression; Depression - drug therapy; Depression - pathology; Gene Expression Regulation - drug effects; Glutamate; Humans; Ketamine - pharmacology; Ketamine - therapeutic use; Models, Biological; Neurogenesis - drug effects; Neurons - drug effects; Rapamycin; Signal Transduction - drug effects; Synapses - drug effects; Synaptogenesis
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.08.044

Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled ‘Anxiety and Depression’. ► Clinical studies demonstrate that ketamine produces a rapid antidepressant response. ► Ketamine rapidly increases synaptogenesis in rodent prefrontal cortex. ► Ketamine-induction of synaptogenesis requires mTOR signaling. ► Ketamine rapidly reverses synaptic loss caused by stress and depression. ► Ketamine results in a functional reconnection of neurons.