Ketamine, an NMDA receptor antagonist that modulates glutamate signaling, rapidly reduces functional connectivity between the default mode network (DMN) and the dorsal nexus, a dorsal medial prefrontal cortex region linked to depression. In a randomized, placebo-controlled, double-blind, crossover resting-state fMRI study in healthy subjects, ketamine decreased connectivity from the DMN's posterior cingulate cortex hub to the dorsal nexus, pregenual anterior cingulate, and medioprefrontal cortex. This subacute modulation at 24 hours overlaps with ketamine's peak antidepressant efficacy in treatment-resistant depression, suggesting that targeting glutamatergic system-driven network dysconnectivity may underlie successful depression treatment.
Ketamine, an NMDA receptor antagonist, reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation in 23 healthy subjects. Reduced amygdala reactivity to negative pictures correlated with resting-state connectivity to the pregenual anterior cingulate cortex. The intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. These findings suggest that modulation of glutamate-responsive circuits, associated with a shift in emotional bias and reduced amygdalo-hippocampal reactivity, may represent an early mechanism to restore disrupted neurobehavioral homeostasis in major depressive disorder.