title: Rapid-onset antidepressant efficacy of glutamatergic system modulators: the neural plasticity hypothesis of depression.
abstract: Depression is a devastating psychiatric disorder widely attributed to deficient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplification. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant efficacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modified indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, 650223, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Jing
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Toledo-Salas
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001921:Brain / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine