Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling

Abstract

NCT#00088699.

A pivot from synaptic monoamine processes to further downstream processes: The impact of ketamine research

“…9 Guided by the revolutionary rapid antidepressant effect ketamine induced, research began pivoting from synaptic cleft processes toward activities further downstream, such as signal transmission and the proteins associated with such. 9,11 An interesting new hypothesis is that ketamine's rapid antidepressant effect points to downstream signal transduction involving the spontaneous transmissions associated with ketamine's action at the NMDA receptor, and it is this NMDA receptormediated neurotransmission (NMDA-receptor blockade) which activates the prompt relief of negative mood symptoms. 11 In contrast to classic antidepressants which were believed to mediate mood symptoms by affecting monoamine neurotransmitter sensitivity, ketamine's hypothesized modus operandi elicits an effective response in an entirely different manner.…”

“…9,11 An interesting new hypothesis is that ketamine's rapid antidepressant effect points to downstream signal transduction involving the spontaneous transmissions associated with ketamine's action at the NMDA receptor, and it is this NMDA receptormediated neurotransmission (NMDA-receptor blockade) which activates the prompt relief of negative mood symptoms. 11 In contrast to classic antidepressants which were believed to mediate mood symptoms by affecting monoamine neurotransmitter sensitivity, ketamine's hypothesized modus operandi elicits an effective response in an entirely different manner. 9,12 Researchers are now suggesting that when ketamine blocks NMDA receptors, this action may stimulate glutamate-release downstream.…”

“…9,12 Researchers are now suggesting that when ketamine blocks NMDA receptors, this action may stimulate glutamate-release downstream. 11,12 This available glutamate then binds to AMPA (A-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid) receptors, precipitating a signal transduction cascade, which in turn activates another pathway that results in synaptic protein synthesis. 9,11 These synaptic proteins produce an increase in dendritic spine density, and it is this proliferation of dendritic spines which is theorized to trigger the rapid antidepressant effect observed with ketamine administration.…”

“…Ketamine acted too quickly in relieving depressive symptoms to act per, until then, widely accepted mechanistic theories based upon cellular processes occurring over weeks to months, not minutes . Guided by the revolutionary rapid antidepressant effect ketamine induced, research began pivoting from synaptic cleft processes toward activities further downstream, such as signal transmission and the proteins associated with such . An interesting new hypothesis is that ketamine's rapid antidepressant effect points to downstream signal transduction involving the spontaneous transmissions associated with ketamine's action at the NMDA receptor, and it is this NMDA receptor‐mediated neurotransmission (NMDA‐receptor blockade) which activates the prompt relief of negative mood symptoms …”

“…In contrast to classic antidepressants which were believed to mediate mood symptoms by affecting monoamine neurotransmitter sensitivity, ketamine's hypothesized modus operandi elicits an effective response in an entirely different manner . Researchers are now suggesting that when ketamine blocks NMDA receptors, this action may stimulate glutamate‐release downstream . This available glutamate then binds to AMPA (A‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptors, precipitating a signal transduction cascade, which in turn activates another pathway that results in synaptic protein synthesis .…”