Ketamine and Other Glutamate Receptor Antagonists As Fast-Actin

The glutamate hypothesis of depression was prominently emerging in this decade. Evidence has shown that low-dose ketamine infusion or intranasal S-ketamine spray exhibited a prominent and rapid antidepressant and antisuicidal effect. A single infusion of 0.5 mg/kg ketamine may achieve up to 70% treatment response in Caucasian patients with treatment-resistant depression (TRD), but only approximately 50% in Taiwanese patients with TRD. The BDNF release and AMPA receptor upregulation via the blockade of NMDA receptor by low-dose ketamine result in the synaptogenesis and neuroplasticity modulation, which may explain the rapid antidepressant effect of low-dose ketamine. Clinical and biological markers, such as depression severity, body mass index, subjective feeling during infusion, and prefrontal cortex (PFC) and anterior cingulate cortex (ACC) functioning, may predict the treatment response of low-dose ketamine infusion. The 18F-FDG-PET studies found that a short activation in the PFC engendered by ketamine infusion may work as a kindler, facilitating the persistent increase in glucose metabolism in the dorsal ACC, which may further explain the outcome that the antidepressant effects of a single infusion of ketamine may be approximately 2 weeks. In recent years, whether several potential glutamate receptor antagonists/modulators, including R-ketamine, ketamine metabolites (i.e., hydroxynorketamine), lanicemine, and D-cycloserine, may also have a fast-acting antidepressant effect is still being studied. However, the exact neuromechanisms of the rapid antidepressant and antisuicidal effects of low-dose ketamine and intranasal S-ketamine spray in the TRD may go beyond the current evidence, which needs further investigation.