Rapid-onset antidepressant efficacy of glutamatergic system modulators:The neural plasticity hypothesis of depression

Depression is a devastating psychiatric disorder widely attributed to defi cient 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 oversimplifi cation. 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 effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning,processes that can be modifi ed 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.