Ketamine increased fronto-striatal functional connectivity in people with treatment-resistant major depression toward levels seen in healthy volunteers, while shifting connectivity in healthy volunteers toward a state similar to depressed participants under placebo. These effects occurred largely without changes in inflammatory markers (C-reactive protein) and were associated with both acute and sustained symptom improvements in the depressed group. Ketamine thus normalized reward-related brain circuitry in depression but disrupted it in healthy individuals, highlighting the potential importance of this circuitry in ketamine's mechanism of action for motivational symptoms.
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
Functional magnetic resonance imaging (fMRI) can identify brain areas linked to depression symptoms and potential treatment targets. A review of fMRI studies on selective serotonin reuptake inhibitors (SSRIs) and ketamine found that both conventional and fast-acting antidepressants normalize amygdala hyperactivity in response to negative emotional stimuli, suggesting a common pathway for antidepressant action. Ketamine's rapid effects on brain activity and connectivity also trend toward normalizing depression-related abnormalities. While fMRI shows promise for identifying treatment targets, improved methodology and study design are needed before its findings can be used as primary clinical trial outcomes.