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Abstract
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.