TL;DR Ketamine’s NMDA antagonism drives glutamate surges, BDNF release, and neuroplasticity, rapidly correcting mood and reward circuit dysfunctions. Human studies show modulated connectivity in ACC and frontolimbic areas linked to antidepressant effects, with transient cognitive dips resolving quickly and no long-term impairment. Dissociative experiences mediate affective changes, enhancing its therapeutic potential for TRD, though safety monitoring is crucial.