Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine

被引:128
作者
Deyama, Satoshi [1 ]
Duman, Ronald S. [2 ]
机构
[1] Kanazawa Univ, Inst Med Pharmaceut & Hlth Sci, Lab Mol Pharmacol, Kanazawa, Ishikawa 9201192, Japan
[2] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06519 USA
关键词
BDNF; Depression; Ketamine; Synaptogenesis; Rapid antidepressants; VEGF-A; ENDOTHELIAL GROWTH-FACTOR; FACTOR VAL66MET POLYMORPHISM; MAJOR DEPRESSIVE DISORDER; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ACTIVITY-DEPENDENT SECRETION; SUBGENUAL PREFRONTAL CORTEX; NMDA RECEPTOR BLOCKADE; D-ASPARTATE ANTAGONIST; TRKB MESSENGER-RNA; FACTOR EXPRESSION;
D O I
10.1016/j.pbb.2019.172837
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
Clinical and preclinical studies have demonstrated that depression, one of the most common psychiatric illnesses, is associated with reduced levels of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), contributing to neuronal atrophy in the prefrontal cortex (PFC) and hippocampus, and reduced hippocampal adult neurogenesis. Conventional monoaminergic antidepressants can block/reverse, at least partially, these deficits in part via induction of BDNF and/or VEGF, although these drugs have significant limitations, notably a time lag for therapeutic response and low response rates. Recent studies reveal that ketamine, an N-methyl-D-aspartate receptor antagonist produces rapid (within hours) and sustained (up to a week) antidepressant actions in both patients with treatment-resistant depression and rodent models of depression. Rodent studies also demonstrate that ketamine rapidly increases BDNF and VEGF release and/or expression in the medial PFC (mPFC) and hippocampus, leading to increase in the number and function of spine synapses in the mPFC and enhancement of hippocampal neurogenesis. These neurotrophic effects of ketamine are associated with the antidepressant effects of this drug. Together, these findings provide evidence for a neurotrophic mechanism underlying the rapid and sustained antidepressant actions of ketamine and pave the way for the development of rapid and more effective antidepressants with fewer side effects than ketamine.
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页数:9
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